Professor Hardev Pandha
Professor of Medical Oncology
Academic and research departments
School of Biosciences and Medicine, Faculty of Health and Medical Sciences.Biography
Hardev Pandha is a clinician scientist and medical oncologist who graduated in medicine at the University of Birmingham. He trained in internal medicine and subsequently in medical oncology at the Royal Postgraduate Medical School at Hammersmith Hospital, London. He completed his PhD (Imperial College) in the Imperial Cancer Research Fund labs at the Hammersmith. He was a visiting fellow at Stanford University prior to completing his medical oncology training at the Royal Marsden Hospital, London. He was a senior lecturer in tumour immunology and medical oncology at St Georges, University of London in 2000 before being appointed Prof of Urological Oncology at the University of Surrey in 2006.
His areas of expertise include the management of patients with Urological cancers and malignant melanoma. He has a key interest in early phase clinical trials involving targeted agents and the translational aspects of novel therapies. His portfolio includes gene and viral therapy as well as immunotherapy and small molecule inhibitors. His laboratory interests reflect this and in particular a combination of novel and biological therapies with more conventional treatments. His lab team have evolved a robust infrastructure of patient sample procurement and biobanking for translational research.
News
In the media
Research
Research interests
- Tumour immunology
- Urological cancer
- Gene therapy
My publications
Publications
Ilett E, Kottke T, Donnelly O, Thompson J, Willmon C, Diaz R, Zaidi S, Coffey M, Selby P, Harrington K, Pandha H, Melcher A, Vile R (2014) Direct, Cytokine-Conditioned, In Vivo Cell Loading for Systemic Delivery of Oncolytic Viruses, MOLECULAR THERAPY 22 pp. S245-S245 NATURE PUBLISHING GROUP
Javed S, Pandha H, Morgan R, Bott S, Eden C, Langley S (2013) Urinary Engrailed-2 (EN2) levels and their correlation with tumour volume and pathological tumour stage in men undergoing radical prostatectomy for prostate cancer, BJU INTERNATIONAL 111 pp. 12-12 WILEY-BLACKWELL
Vidal L, Pandha H, Spicer J, Harrington KJ, Allen S, Leader D, Coffey M, Thompson B, Kaye S, De-Bono J (2006) A phase I study of reolysin given intravenously to patients with advanced malignancies., JOURNAL OF CLINICAL ONCOLOGY 24 (18) pp. 136S-136S AMER SOC CLINICAL ONCOLOGY
Quatan N, Meyer B, Bailey M, Pandha H (2006) Persistently high levels of immunosuppressive cytokines in patients after radical prostatectomy, PROSTATE CANCER AND PROSTATIC DISEASES 9 (4) pp. 420-425 NATURE PUBLISHING GROUP
Boisgerault N, Kottke T, Pulido J, Thompson J, Diaz RM, Rommelfanger-Konkol D, Embry A, Saenz D, Poeschla E, Pandha H, Harrington K, Melcher A, Selby P, Vile R (2013) Functional cloning of recurrence-specific antigens identifies molecular targets to treat tumor relapse, Molecular Therapy 21 (8) pp. 1507-1516
Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-II± (TOPO-II±) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-II± compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors - across histologies and primary treatments - express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor. © The American Society of Gene & Cell Therapy.
Heinemann L, Simpson G, Harrington K, Melcher A, Coffey MC, Pandha HS (2008) Synergistic anti-tumour activity of oncolytic Reovirus and cisplatin in a B16.F10 mouse melanoma model, EJC SUPPLEMENTS 6 (12) pp. 99-99 PERGAMON-ELSEVIER SCIENCE LTD
Pandha H, Sorensen KD, Orntoft TF, Langley S, Hoyer S, Borre M, Morgan R (2012) Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer, BJU International 110 (6B)
OBJECTIVES To evaluate the relationship between levels of a recently described prostate cancer biomarker engrailed-2 (EN2) in urine and cancer volume in men who had undergone radical prostatectomy (RP) for prostate cancer. To date, prostate-specific antigen (PSA) levels have not reliably predicted prostate cancer volume. Reliable volume indicator biomarker(s) may aid management decisions, e.g. active treatment vs active surveillance. Patients and Methods Archived patient samples from the Aarhus Prostate Cancer Project, Denmark, were assessed. Pre-treatment mid-stream urines, without preceding prostatic massage, were collected and stored at -80 °C. Urinary EN2 levels were measured by a recently published enzyme-linked immunosorbent assay. Results In all, 88 of the whole cohort of 125 men (70%) were positive for EN2 in their urine (>42.5 ¼g/L); 38/58 (65%) men where cancer volume data was available. There was no statistical relationship between urinary EN2 levels and serum PSA levels. PSA levels did not correlate with tumour stage, combined Gleason grade, total prostatic weight or cancer volume. There was a strong statistical relationship between urinary EN2 and prostate cancer volume by linear regression (P= 0.006). Higher EN2 levels correlated with tumour stage T1 vs T2 (P= 0.027). Conclusions Pre-surgical urinary EN2 levels were associated with increasing tumour stage and closely reflected the volume of cancer in RP specimens. Given the ease of collection (no prostatic massage required) and the simplicity, low cost and robustness of the assay, EN2 may become a useful biomarker in not only identifying which patients have prostate cancer but may also facilitate risk stratification by indicating the burden of tumour volume. © 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.
Michael A, John J, Meyer B, Pandha H (2010) Activation and Genetic Modification of Human Monocyte-Derived Dendritic Cells using Attenuated Salmonella typhimurium, THESCIENTIFICWORLDJOURNAL 10 pp. 393-401 THESCIENTIFICWORLD LTD
Prestwich RJ, Errington F, Diaz RM, Pandha HS, Harrington KJ, Melcher AA, Vile RG (2009) The Case of Oncolytic Viruses Versus the Immune System: Waiting on the Judgment of Solomon, HUMAN GENE THERAPY 20 (10) pp. 1119-1132 MARY ANN LIEBERT INC
Blanchard M, Shim KG, Grams MP, Rajani K, Diaz RM, Furutani KM, Thompson J, Olivier KR, Park SS, Markovic SN, Pandha H, Melcher A, Harrington K, Zaidi S, Vile R (2015) Definitive Management of Oligometastatic Melanoma in a Murine Model Using Combined Ablative Radiation Therapy and Viral Immunotherapy, INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS 93 (3) pp. 577-587 ELSEVIER SCIENCE INC
Gore ME, Nutting CM, Pandha HS, Melcher AA, Vile RG, Harrington KJ (2008) T-cell responses to survivin in cancer patients undergoing radiation therapy, Clinical Cancer Research 14 (15) pp. 4883-4883
Rajani K, Shim K, Parrish C, Ilett L, Kottke T, Pulido J, Thompson J, Pandha H, Harrington K, Melcher A, Errington F, Diaz R, Coffey M, Zaidi S, Vile R (2015) Combination Therapy of Reovirus and PD-1 Blockade Effectively Establishes Tumor Control Via Innate and Adaptive Immune Responses, MOLECULAR THERAPY 23 pp. S30-S30 NATURE PUBLISHING GROUP
Eisenberger MA, Hardy-Bessard A-C, Mourey L, Mainwaring PN, Ford D, Shapiro JD, Carles J, Ng S, Gil T, Alekseev B, Ivanov S, Facchini T, Legouffe E, Apolikhin O, Pandha HS, Beeker A, Karyakin O, Zhang W, Chadjaa M, De Bono JS (2012) Comparison of two doses of cabazitaxel plus prednisone in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel (D)-containing regimen, JOURNAL OF CLINICAL ONCOLOGY 30 (15) AMER SOC CLINICAL ONCOLOGY
Karapanagiotou E, Pandha HS, Hall G, Chester J, Melcher A, Coffey M, de Bono J, Gore ME, Nutting CM, Harrington KJ (2009) Phase I/II trial of oncolytic reovirus (Reolysin) in combination with carboplatin/paclitaxel in patients (pts) with advanced solid cancers, JOURNAL OF CLINICAL ONCOLOGY 27 (15) AMER SOC CLINICAL ONCOLOGY
Donnelly OG, Errington-Mais F, Steele L, Hadac E, Jennings V, Scott K, Peach H, Phillips RM, Bond J, Pandha H, Harrington K, Vile R, Russell S, Selby P, Melcher AA (2013) Measles virus causes immunogenic cell death in human melanoma, Gene Therapy 20 (1) pp. 7-15
Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response. © 2013 Macmillan Publishers Limited All rights reserved.
Pencavel T, Seth R, Hayes A, Melcher A, Pandha H, Vile R, Harrington KJ (2010) Locoregional intravascular viral therapy of cancer: precision guidance for Paris's arrow?, GENE THERAPY 17 (8) pp. 949-960 NATURE PUBLISHING GROUP
Verbeke CS, Hamdan S, Booth J, Pandha HS, Blair GE (2006) Limited expression of the Coxsackie and Adenovirus Receptor in pancreatic cancer may reduce suitability of adenoviral gene therapy, JOURNAL OF PATHOLOGY 210 pp. 2-2 JOHN WILEY & SONS LTD
Hamdan S, Verbeke CS, Fox N, Booth J, Bottley G, Pandha HS, Blair GE (2011) The roles of cell surface attachment molecules and coagulation Factor X in adenovirus 5-mediated gene transfer in pancreatic cancer cells., Cancer Gene Ther 18 (7) pp. 478-488
Transduction of 11 pancreatic cancer cell lines with a replication-deficient adenovirus 5 expressing enhanced green fluorescent protein (Ad5EGFP) was analyzed and variable EGFP levels were observed, ranging from
Kelly ZL, Michael A, Butler-Manuel S, Pandha HS, Morgan RG (2011) HOX genes in ovarian cancer., J Ovarian Res 4
ABSTRACT: The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.
Enting D, Lannitto ML, Pandha HS, Eberi M, Chowdhury S, Hayday AC (2014) Effects of concomitant therapies on gamma delta T-cell responses to zoledronate in patients with advanced prostate cancer, JOURNAL OF CLINICAL ONCOLOGY 32 (15) AMER SOC CLINICAL ONCOLOGY
Javed S, Morgan R, Hindley R, Bott S, Eden C, Pandha H, Langley S (2014) Urinary engrailed-2 levels in healthy volunteers, patients on active surveillance and following radical prostate cancer treatment, BJU INTERNATIONAL 113 pp. 43-44 WILEY-BLACKWELL
Pandha HS, Harrington KJ, Vile RG (2008) Viral Therapy of Cancer, John Wiley
Michael A, Kelly ZL, Moller-Levet CS, Pandha H, Morgan R (2014) HOX GENE EXPRESSION IN OVARIAN CANCER, ANTICANCER RESEARCH 34 (10) pp. 6058-6059 INT INST ANTICANCER RESEARCH
Annels NE, Shaw VE, Gabitass RF, Billingham L, Corrie P, Eatock M, Valle J, Smith D, Wadsley J, Cunningham D, Pandha H, Neoptolemos JP, Middleton G (2013) The effects of gemcitabine and capecitabine combination chemotherapy and of low-dose adjuvant GM-CSF on the levels of myeloid-derived suppressor cells in patients with advanced pancreatic cancer., Cancer Immunol Immunother 63 (2) pp. 175-183
In pre-clinical models, the only two chemotherapy drugs which have been demonstrated to directly reduce the number of myeloid-derived suppressor cells (MDSCs) are gemcitabine and 5-fluorouracil. Here we analyze the dynamics of MDSCs, phenotyped as Lin-DR-CD11b+, in patients with advanced pancreatic cancer receiving the combination of gemcitabine and capecitabine, a 5-FU pro-drug. We found no evidence that gemcitabine and capecitabine directly reduce MDSC% in patients. Gemcitabine and capecitabine reduced MDSCs in 42% of patients (n = 19) and MDSC% fell in only 3/9 patients with above-median baseline MDSCs. In 5/8 patients with minimal tumour volume change on treatment, the MDSC% went up: increases in MDSC% in these patients appeared to correlate with sustained cancer-related inflammatory cytokine upregulation. In a separate cohort of 21 patients treated with gemcitabine and capecitabine together with concurrently administered GV1001 vaccine with adjuvant GM-CSF, the MDSC% fell in 18/21 patients and there was a significant difference in the trajectory of MDSCs between those receiving GV1001 and GM-CSF in combination with chemotherapy and those receiving chemotherapy alone. Thus, there was no evidence that the addition of low-dose adjuvant GM-CSF increased Lin-DR-CD11b+ MDSC in patients receiving combination chemoimmunotherapy. 9/21 patients developed an immune response to GV1001 and the MDSCs fell in 8 of these 9 patients, 6 of whom had above-median pre-vaccination MDSC levels. A high pre-vaccination MDSC% does not preclude the development of immunity to a tumour-associated antigen.
Crabb SJ, Douglas J, Annels NE, Morgan R, Packham G, Pandha HS (2014) Engrailed-2 (EN2) protein expression and prognosis in bladder cancer following radical cystectomy (RC)., JOURNAL OF CLINICAL ONCOLOGY 32 (15) AMER SOC CLINICAL ONCOLOGY
Derhovanessian E, Adams V, Haehnel K, Groeger A, Pandha H, Ward S, Pawelec G (2009) Pretreatment frequency of circulating IL-17(+)CD4(+) T-cells, but not Tregs, correlates with clinical response to whole-cell vaccination in prostate cancer patients, INTERNATIONAL JOURNAL OF CANCER 125 (6) pp. 1372-1379 WILEY-BLACKWELL
Errico MC, Felicetti F, Bottero L, Mattia G, Boe A, Felli N, Petrini M, Bellenghi M, Pandha HS, Calvaruso M, Tripodo C, Colombo MP, Morgan R, Care A (2013) The abrogation of the HOXB7/PBX2 complex induces apoptosis in melanoma through the miR-221&222-c-FOS pathway, INTERNATIONAL JOURNAL OF CANCER 133 (4) pp. 879-892 WILEY-BLACKWELL
Cutaneous melanoma is the fastest increasing cancer worldwide. Although several molecular abnormalities have been associated with melanoma progression, the underlying mechanisms are still largely unknown and few targeted therapies are under evaluation. Here we show that the HOXB7/PBX2 dimer acts as a positive transcriptional regulator of the oncogenic microRNA-221 and -222. In addition, demonstrating c-FOS as a direct target of miR-221&222, we identify a HOXB7/PBX2miR-221&222 c-FOS regulatory link, whereby the abrogation of functional HOXB7/PBX2 dimers leads to reduced miR-221&222 transcription and elevated c-FOS expression with consequent cell death. Taking advantage of the treatment with the peptide HXR9, an antagonist of HOX/PBX dimerization, we recognize miR-221&222 as effectors of its action, in turn confirming the HXR9 efficacy in the treatment of human melanoma malignancy, whilst sparing normal human melanocytes. Our findings, besides suggesting the potential therapeutic of HXR9 or its derivatives in malignant melanoma, suggest the disruption of the HOXB7/PBX2 complexes, miR-221&222 inhibition or even better their combination, as innovative therapeutic approaches. What's new? Cutaneous melanoma is the fastest increasing cancer worldwide. Although several molecular abnormalities have been associated with melanoma progression, the underlying mechanisms are still largely unknown. Here the authors show that the HOXB7/PBX2 complex is a new transcriptional activator of the oncogenic microRNA-221 and 222 in melanoma inducing tumor malignancy. The authors also identified c-FOS as a direct target of miR-221&222 whose repression causes reduced apoptosis. The abrogation of HOXB7 and/or miR-221&222 or the disruption of HOXB7/PBX2 dimers by the peptide HXR9 might thus represent novel molecular approaches for advanced melanoma, an aggressive neoplasm refractory to traditional therapies. Copyright © 2013 UICC.
Amin Al Olama A, Dadaev T, Hazelett DJ, Li Q, Leongamornlert D, Saunders EJ, Stephens S, Cieza-Borrella C, Whitmore I, Benlloch Garcia S, Giles GG, Southey MC, Fitzgerald L, Gronberg H, Wiklund F, Aly M, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TL, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw KT, Stanford JL, Thibodeau SN, Mcdonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, WokoBorczyk D, Kluzniak W, Cannon-Albright L, Brenner H, Butterbach K, Arndt V, Park JY, Sellers T, Lin HY, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Govindasami K, Guy M, Lophatonanon A, Muir K, Viñuela A, Brown AA, PRACTICAL Consortium, COGS-CRUK GWAS-ELLIPSE (Part of GAME-ON) Initiative, Australian Prostate Cancer BioResource, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, Freedman M, Conti DV, Easton D, Coetzee GA, Eeles RA, Kote-Jarai Z (2015) Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans., Hum Mol Genet 24 (19) pp. 5589-5602
Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain
Rajani K, Parrish C, Kottke T, Thompson J, Zaidi S, Ilett L, Shim KG, Diaz R-M, Pandha H, Harrington K, Coffey M, Melcher A, Vile R (2015) Combination Therapy With Reovirus and Anti-PD-1 Blockade Controls Tumor Growth Through Innate and Adaptive Immune Responses, MOLECULAR THERAPY 24 (1) pp. 166-174 NATURE PUBLISHING GROUP
Kottke T, Errington F, Pulido J, Galivo F, Thompson J, Wongthida P, Diaz RM, Chong H, Ilett E, Chester J, Pandha H, Harrington K, Selby P, Melcher A, Vile R (2011) Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors., Nat Med 17 (7) pp. 854-859
Effective cancer immunotherapy requires the release of a broad spectrum of tumor antigens in the context of potent immune activation. We show here that a cDNA library of normal tissue, expressed from a highly immunogenic viral platform, cures established tumors of the same histological type from which the cDNA library was derived. Immune escape occurred with suboptimal vaccination, but tumor cells that escaped the immune pressure were readily treated by second-line virus-based immunotherapy. This approach has several major advantages. Use of the cDNA library leads to presentation of a broad repertoire of (undefined) tumor-associated antigens, which reduces emergence of treatment-resistant variants and also permits rational, combined-modality approaches in the clinic. Finally, the viral vectors can be delivered systemically, without the need for tumor targeting, and are amenable to clinical-grade production. Therefore, virus-expressed cDNA libraries represent a novel paradigm for cancer treatment addressing many of the key issues that have undermined the efficacy of immuno- and virotherapy to date.
Twigger K, Roulstone V, Kyula J, Karapanagiotou EM, Syrigos KN, Morgan R, White C, Bhide S, Nuovo G, Coffey M, Thompson B, Jebar A, Errington F, Melcher AA, Vile RG, Pandha HS, Harrington KJ (2012) Reovirus exerts potent oncolytic effects in head and neck cancer cell lines that are independent of signalling in the EGFR pathway., BMC Cancer 12
Reovirus exploits aberrant signalling downstream of Ras to mediate tumor-specific oncolysis. Since ~90% squamous cell carcinomas of the head and neck (SCCHN) over-express EGFR and SCCHN cell lines are sensitive to oncolytic reovirus, we conducted a detailed analysis of the effects of reovirus in 15 head and neck cancer cell lines. Both pre- and post-entry events were studied in an attempt to define biomarkers predictive of sensitivity/resistance to reovirus. In particular, we analysed the role of EGFR/Ras signalling in determining virus-mediated cytotoxicity in SCCHN.
Ismail M, Morgan R, Harrington K, Davies J, Pandha H (2009) Enhancing prostate cancer cryotherapy using tumour necrosis factor related apoptosis-inducing ligand (TRAIL) sensitisation in an in vitro cryotherapy model, CRYOBIOLOGY 59 (2) pp. 207-213 ACADEMIC PRESS INC ELSEVIER SCIENCE
John J, Ismail M, Riley C, Askham J, Morgan R, Melcher A, Pandha H (2010) Differential effects of Paclitaxel on dendritic cell function, BMC IMMUNOLOGY 11 ARTN 14 BIOMED CENTRAL LTD
Pandha H, Melcher A, Harrington K, Vile R (2009) 5th international meeting on replicating oncolytic virus therapeutics Banff, Alberta, Canada, 18-22 March 2009, Molecular Therapy 17 (6) pp. 934-935
Prestwich RJ, Scott KJ, Brown J, Harnden P, Whelan P, Cartledge J, O'Donnell D, Pandha HS, Selby PJ, Banks RE, Merrick AE, Melcher AA (2009) The feasibility of establishing a programme of adjuvant autologous vaccination for renal cell carcinoma, BJU INTERNATIONAL 103 (6) pp. 740-746 WILEY-BLACKWELL PUBLISHING, INC
Plowright L, Shears L, Pandha H, Morgan R (2007) Disrupting the interaction between Hox and PBX causes apoptotic cell death and reduces in vivo proliferation of a non-small cell lung cancer model, MOLECULAR CANCER THERAPEUTICS 6 (12) pp. 3504S-3504S AMER ASSOC CANCER RESEARCH
Michael A, Pandha H (2013) Presentation and Symptomatology of Prostate Cancer, In: Tewari AK (eds.), Prostate Cancer: A Comprehensive Perspective 38 pp. 467-471 Springer Science & Business Media
27. Introduction. In 2010, 217,730 men will have been diagnosed with prostate
cancer (PCa) in the United States of America (USA), and around 32,730 will have
died from the disease [1]. Depending on the extent of prostate-specific antigen ...
cancer (PCa) in the United States of America (USA), and around 32,730 will have
died from the disease [1]. Depending on the extent of prostate-specific antigen ...
Seth R, Khan AA, Pencavel TD, Wilkinson MJ, Kyula JN, Simpson G, Pandha H, Melcher A, Vile R, Harris PA, Harrington KJ (2015) Adenovirally delivered enzyme prodrug therapy with herpes simplex virus-thymidine kinase in composite tissue free flaps shows therapeutic efficacy in rat models of glioma., Plast Reconstr Surg 135 (2) pp. 475-487
INTRODUCTION: Free flap gene therapy exploits a novel therapeutic window when viral vectors can be delivered into a flap ex vivo. The authors investigated the therapeutic potential of an adenovirally-delivered thymidine kinase/ganciclovir prodrug system expressed following vector delivery into a free flap. METHODS: The authors demonstrated direct in vitro cytotoxicity by treating a panel of malignant cell lines with the thymidine kinase/ganciclovir system and demonstrated significant cell kill proportional to the multiplicity of infection of adenoviral vector expressing thymidine kinase. Bystander cytotoxicity was demonstrated using conditioned media from producer cells (expressing adenovirally-delivered thymidine kinase and treated with ganciclovir) to demonstrate cytotoxicity in naive tumor cells. The authors investigated the effect of adenoviral vector expressing thymidine kinase/ganciclovir therapy in vivo, using models of microscopic and macroscopic residual disease in a rodent superficial inferior epigastric artery flap model. RESULTS: The authors observed retardation of tumor volume growth in both microscopic (p = 0.0004) and macroscopic (p = 0.0005) residual disease models and prolongation of animal survival. Gene expression studies demonstrated that viral genomic material was found predominantly in flap tissues but declined over time. CONCLUSIONS: The authors describe the utility of virally delivered enzyme/prodrug therapy, using a free flap as a vehicle for delivery. They discuss the merits and limitations of this approach and the unique role of therapeutic free flaps among reconstructive techniques available to the plastic surgeon.
Simpson GR, Relph KL, Harrington K, Melcher A, Pandha H (2016) Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances, Oncolytic Virotherapy 2016 (5) pp. 1-13 Dove Medical Press
Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.
Annels NE, Simpson GR, Denyer M, McGrath SE, Falgari G, Killick E, Eeles R, Stebbing J, Pchejetski D, Cutress R, Murray N, Michael A, Pandha H (2014) Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer., Clin Exp Immunol 177 (2) pp. 428-438
We reported the expression of the homeodomain-containing transcription factor Engrailed-2 (EN2) in prostate cancer and showed that the presence of EN2 protein in the urine was highly predictive of prostate cancer. This study aimed to determine whether patients with prostate cancer have EN2 autoantibodies, what the prevalence of these antibodies is and whether they are associated with disease stage. The spontaneous immunoglobulin (Ig)G immune response against EN2 and for comparison the tumour antigen New York Esophageal Squamous Cell Carcinoma 1 (NY-ESO-1), were tested by enzyme-linked immunosorbent assay (ELISA) in three different cohorts of prostate cancer patients as well as a group of men genetically predisposed to prostate cancer. Thirty-two of 353 (9·1%) of the SUN cohort representing all stages of prostate cancer demonstrated EN2 IgG responses, 12 of 107 patients (11·2%) in the advanced prostate cancer patients showed responses, while only four of 121 patients (3·3%) with castrate-resistant prostate cancer showed EN2 autoantibodies. No significant responses were found in the predisposed group. Anti-EN2 IgG responses were significantly higher in patients with prostate cancer compared to healthy control males and similarly prevalent to anti-NY-ESO-1 responses. While EN2 autoantibodies are not a useful diagnostic or monitoring tool, EN2 immunogenicity provides the rationale to pursue studies using EN2 as an immunotherapeutic target.
Boisgerault N, Kottke T, Thompson J, Diaz RM, Rommelfanger-Konkol D, Embry A, Saenz D, Poeschla E, Pulido J, Vile R, Pandha H, Harrington K, Melcher A, Selby P (2013) Functional Cloning of Recurrence-specific Antigens Identifies Molecular Targets to Treat Tumor Relapse, Molecular Therapy
Aggressive regrowth of recurrent tumors following treatment-induced dormancy represents a major clinical challenge for treatment of malignant disease. We reported previously that recurrent prostate tumors, which underwent complete macroscopic regression followed by aggressive regrowth, could be cured with a vesicular stomatitis virus (VSV)-expressed cDNA library derived from recurrent tumor cells. By screening the protective, recurrence-derived VSV-cDNA library, here we identify topoisomerase-II± (TOPO-II±) as a recurrence-specific tumor antigen against which tolerance can be broken. Tumor recurrences, in two different types of tumor (prostate and melanoma), which had evaded two different frontline treatments (immunotherapy or chemotherapy), significantly overexpressed TOPO-II± compared with their primary tumor counterparts, which conferred a novel sensitivity to doxorubicin (DOX) chemotherapy upon the recurrent tumors. This was exploited in vivo using combination therapies to cure mice, which would otherwise have relapsed, after suboptimal primary therapy in both models. Our data show that recurrent tumors-across histologies and primary treatments-express distinct antigens compared with the primary tumor which can be identified using the VSV-cDNA library technology. These results suggest that it may be possible to design a few common second-line therapies against a variety of tumor recurrences, in some cases using agents with no obvious activity against the primary tumor.Molecular Therapy (2013); doi:10.1038/mt.2013.116.
Michael A, Relph K, Pandha H (2010) Emergence of potential biomarkers of response to anti-angiogenic anti-tumour agents, INTERNATIONAL JOURNAL OF CANCER 127 (6) pp. 1251-1258 WILEY-BLACKWELL
Hu JCC, Coffin RS, Davis CJ, Graham NJ, Groves N, Guest PJ, Harrington KJ, James ND, Love CA, McNeish I, Medley LC, Michael A, Nutting CM, Pandha HS, Shorrock CA, Simpson J, Steiner J, Steven NM, Wright D, Coombes RC (2006) A phase I study of OncoVEX(GM-CSF), a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor, CLINICAL CANCER RESEARCH 12 (22) pp. 6737-6747 AMER ASSOC CANCER RESEARCH
Brunner C, Davies NM, Martin RM, Eeles R, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles G, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Donovan J, Hamdy FC, Pashayan N, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha HS, PRACTICAL Consortium, Zuccolo L (2016) Alcohol Consumption and Prostate Cancer Incidence and Progression: a Mendelian Randomization Study, International Journal of Cancer
Prostate cancer is the most common cancer in men in developed countries, and is a target for risk reduction strategies. The effects of alcohol consumption on prostate cancer incidence and survival remain unclear, potentially due to methodological limitations of observational studies. In the current study we investigated the associations of genetic variants in alcohol-metabolising genes with prostate cancer incidence and survival.
Lunt C, Barber N, Montgomery A, Kalsi V, Parker T, Michael A, Pandha H, Hindley R (2010) CYTOREDUCTIVE NEPHRECTOMY IN THE TYROKINASE INHIBITOR ERA, J ENDOUROL 24 pp. A303-A303 MARY ANN LIEBERT INC
Middleton GW, Annels NE, Pandha HS (2012) Are we ready to start studies of Th17 cell manipulation as a therapy for cancer?, Cancer Immunol Immunother 61 (1) pp. 1-7
From a therapeutic perspective, the bourgeoning literature on Th17 cells should allow us to decide whether to rationally pursue the manipulation of Th17 cells in cancer. The purpose of this review is to attempt a synthesis of a number of contradictory conclusions as to the role that these cells are playing in the process of tumourigenesis in order to provide guidance as to whether our current understanding is sufficient to safely pursue Th17-targeted therapy in cancer at this time. Th17 cells are a highly plastic population and the cytokine drivers for Th17 cell generation and skewing will vary between various cancers and importantly between different sites of tumour involvement in any individual patient. The net impact of the pro-angiogenic IL-17 produced not only by Th17 cells but by other cells particularly macrophages and the anti-tumour effects of Th1/Th17 cells will in turn be determined by the complex interplay of diverse chemokines and cytokines in any tumour microenvironment. Th17 cells that fail to home to tumours may be immunosuppressive. The complexity of IL-17 and Th17 dynamics makes easy prediction of the effects of either enhancing or suppressing Th17 cell differentiation in cancer problematic.
Prestwich RJ, Errington F, Steele LP, Ilett EJ, Morgan RSM, Harrington KJ, Pandha HS, Selby PJ, Vile RG, Melcher AA (2009) Reciprocal Human Dendritic Cell-Natural Killer Cell Interactions Induce Antitumor Activity Following Tumor Cell Infection by Oncolytic Reovirus, JOURNAL OF IMMUNOLOGY 183 (7) pp. 4312-4321 AMER ASSOC IMMUNOLOGISTS
Vidal L, Pandha HS, Yap TA, White CL, Twigger K, Vile RG, Melcher A, Coffey M, Harrington KJ, DeBono JS (2008) A Phase I Study of Intravenous Oncolytic Reovirus Type 3 Dearing in Patients with Advanced Cancer, CLINICAL CANCER RESEARCH 14 (21) pp. 7127-7137 AMER ASSOC CANCER RESEARCH
Yap TA, Vidal L, Pandha H, Spicer J, Digue L, Coffey M, Thompson B, Kaye SB, Harrington KJ, De-Bono JS (2006) A phase I study of wild-type reovirus, which selectively replicates in cells expressing activated Ras, administered intravenously to patients with advanced cancer, EJC SUPPLEMENTS 4 (12) pp. 108-108 PERGAMON-ELSEVIER SCIENCE LTD
Comins C, Simpson GR, Relph K, Harrington KJ, Melcher A, Pandha H (2013) Reoviral Therapy for Cancer: Strategies for Improving Antitumor Efficacy Using Radio- and Chemotherapy, pp. 185-198
Reovirus type 3 Dearing (Reolysin, Oncolytics Biotech) is a wild-type double-stranded RNA virus that is ubiquitous and nonpathogenic in humans. It has been shown to be oncolytic by its ability to replicate in transformed cells but not in normal cells. Reovirus has been shown to exert significant antitumor effects in both preclinical in vitro and in vivo studies. In addition, reovirus can activate both innate and adaptive antitumor response against human and murine tumors. However, despite antitumor activity, the responses to reovirus monotherapy in human trials have been modest and short-lived. As a result, a number of potential strategies for improving antitumor efficacy are currently being evaluated. This chapter describes the application of oncolytic reovirus as an anticancer agent, alone or in combination with conventional therapies such as radiotherapy and chemotherapeutics. It also summarizes current clinical trials on reovirus therapy. © 2014 Elsevier Inc. All rights reserved.
Alonso-Camino V, Rajani K, Kottke T, Rommelfanger-Konkol D, Zaidi S, Thompson J, Pulido J, Ilett L, Selby P, Pandha H, Melcher A, Harrington K, Diaz R, Vile R (2014) The Profile of Tumor Antigens Which Can Be Targeted By Immunotherapy Depends Upon the Tumor's Anatomical Site, MOLECULAR THERAPY 22 pp. S200-S200 NATURE PUBLISHING GROUP
Roulstone V, Pedersen M, Kyula J, Mansfield D, Khan AA, McEntee G, Wilkinson M, Karapanagiotou E, Coffey M, Marais R, Jebar A, Errington-Mais F, Melcher A, Vile R, Pandha H, McLaughlin M, Harrington KJ (2015) BRAF- and MEK-Targeted Small Molecule Inhibitors Exert Enhanced Antimelanoma Effects in Combination With Oncolytic Reovirus Through ER Stress., Mol Ther 23 (5) pp. 931-942
Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma).
Pandha H, Rigg A, John J, Lemoine N (2007) Loss of expression of antigen-presenting molecules in human pancreatic cancer and pancreatic cancer cell lines, CLINICAL AND EXPERIMENTAL IMMUNOLOGY 148 (1) pp. 127-135 BLACKWELL PUBLISHING
Michael A, Coward J, Brown A, Barber N, Pandha H (2015) The tolerability of sunitinib in elderly patients with metastatic renal cancer., Clin Oncol (R Coll Radiol) 27 (6) pp. 371-372
Mackenzie Ross AD, Cook MG, Chong H, Hossain M, Pandha HS, Bennett DC (2013) Senescence evasion in melanoma progression: Uncoupling of DNA-damage signaling from p53 activation and p21 expression, Pigment Cell and Melanoma Research 26 (2) pp. 226-235
The best-established function of the melanoma-suppressor p16 is mediation of cell senescence, a permanent arrest following cell proliferation or certain stresses. The importance of p16 in melanoma suggests indolence of the other major senescence pathway through p53. Little or no p53 is expressed in senescent normal human melanocytes, but p16-deficient melanocytes can undergo p53-mediated senescence. As p16 expression occurs in nevi but falls with progression toward melanoma, we here investigated whether p53-dependent senescence occurs at some stage and, if not, what defects were detectable in this pathway, using immunohistochemistry. Phosphorylated checkpoint kinase 2 (CHEK2) can mediate DNA-damage signaling, and under some conditions senescence, by phosphorylating and activating p53. Remarkably, we detected no prevalent p53-mediated senescence in any of six classes of lesions. Two separate defects in p53 signaling appeared common: in nevi, lack of p53 phosphorylation by activated CHEK2, and in melanomas, defective p21 upregulation by p53 even when phosphorylated. © 2012 John Wiley & Sons A/S.
Alonso-Camino V, Rajani K, Kottke T, Rommelfanger-Konkol D, Zaidi S, Thompson J, Pulido J, Ilett E, Donnelly O, Selby P, Pandha H, Melcher A, Harrington K, Diaz RM, Vile R (2014) The Profile of Tumor Antigens Which Can be Targeted by Immunotherapy Depends Upon the Tumor's Anatomical Site, MOLECULAR THERAPY 22 (11) pp. 1936-1948 NATURE PUBLISHING GROUP
Mansfield D, Pencavel T, Kyula JN, Zaidi S, Roulstone V, Thway K, Karapanagiotou L, Khan AA, McLaughlin M, Touchefeu Y, Seth R, Melcher AA, Vile RG, Pandha HS, Harrington KJ (2012) Oncolytic Vaccinia virus and radiotherapy in head and neck cancer., Oral Oncol
OBJECTIVE: Oncolytic forms of attenuated Vaccinia virus are now in clinical development, assessing the compatibility of this novel treatment with radiotherapy may reveal exploitable synergistic relationships. MATERIALS AND METHODS: In vitro analyses of cell killing, cell cycle effects and caspase activation were carried out on HN3, HN5, CAL27, Detroit, SIHN5B, and PJ41 cells. In vivo studies of the virus and X-radiation were performed on H&N xenografts in CD1 nude mice. RESULTS: Cell killing in vitro was demonstrated to be dose- and time-dependent. Infection causes an increase in S-phase and sub-G1 cells. A dose dependent increase in active caspase-3 indicated induction of apoptosis. Xenografts injected with Vaccinia stabilised and frequently completely regressed. Combination with radiation generated additional cell death, induction of caspase activity and in vivo further improved long term regression rates. CONCLUSIONS: These data support continued exploration of this therapy combination and indicates potential for clinical trials in head and neck cancer.
Shears L, Plowright L, Harrington K, Pandha HS, Morgan R (2008) Disrupting the Interaction Between HOX and PBX Causes Necrotic and Apoptotic Cell Death in the Renal Cancer Lines CaKi-2 and 769-P, JOURNAL OF UROLOGY 180 (5) pp. 2196-2201 ELSEVIER SCIENCE INC
Middleton GW, Annels NE, Pandha HS (2011) Are we ready to start studies of Th17 cell manipulation as a therapy for cancer?, Cancer Immunology, Immunotherapy pp. 1-7
Zaidi S, Blanchard M, Shim K, Ilett E, Rajani K, Parrish C, Boisgerault N, Kottke T, Thompson J, Celis E, Pulido J, Selby P, Pandha H, Melcher A, Harrington K, Vile R (2015) Mutated BRAF emerges as a major effector of recurrence in a murine melanoma model after treatment with immunomodulatory agents, Molecular Therapy 23 (5) pp. 845-856
© 2015 The American Society of Gene & Cell Therapy.We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-II±, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF-specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence.
Harrington KJ, Karapanagiotou EM, Roulstone V, Twigger KR, White CL, Vidal L, Beirne D, Prestwich R, Newbold K, Ahmed M, Thway K, Nutting CM, Coffey M, Harris D, Vile RG, Pandha HS, DeBono JS, Melcher AA (2010) Two-Stage Phase I Dose-Escalation Study of Intratumoral Reovirus Type 3 Dearing and Palliative Radiotherapy in Patients with Advanced Cancers, CLINICAL CANCER RESEARCH 16 (11) pp. 3067-3077 AMER ASSOC CANCER RESEARCH
Brend T, Kelly Z, Ajaz M, Morgan R, Pandha H, Short SC (2014) THERAPEUTIC POTENTIAL OF TARGETING HOX PROTEIN FUNCTION IN GLIOBLASTOMA, NEURO-ONCOLOGY 16 OXFORD UNIV PRESS INC
Taylor AE, Martin RM, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Pashayan N, Khaw KT, Blott W, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon?Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha HS, PRACTICAL Consortium, Donovan J, Munafo MR (2016) Investigating the possible causal role of coffee consumption with prostate cancer risk and progression using Mendelian randomization analysis, International Journal of Cancer
Coffee consumption has been shown in some studies to be associated with lower risk of prostate cancer. However, it is unclear if this association is causal or due to confounding or reverse causality. We conducted a Mendelian randomisation analysis to investigate the causal effects of coffee consumption on prostate cancer risk and progression. We used two genetic variants robustly associated with caffeine intake (rs4410790 and rs2472297) as proxies for coffee consumption in a sample of 46,687 men of European ancestry from 25 studies in the PRACTICAL consortium. Associations between genetic variants and prostate cancer case status, stage and grade were assessed by logistic regression and with all-cause and prostate cancer-specific mortality using Cox proportional hazards regression. There was no clear evidence that a genetic risk score combining rs4410790 and rs2472297 was associated with prostate cancer risk (OR per additional coffee increasing allele: 1.01, 95% CI: 0.98,1.03) or having high-grade compared to low-grade disease (OR: 1.01, 95% CI: 0.97,1.04). There was some evidence that the genetic risk score was associated with higher odds of having nonlocalised compared to localised stage disease (OR: 1.03, 95% CI: 1.01, 1.06). Amongst men with prostate cancer, there was no clear association between the genetic risk score and all-cause mortality (HR: 1.00, 95% CI: 0.97,1.04) or prostate cancer-specific mortality (HR: 1.03, 95% CI: 0.98,1.08). These results, which should have less bias from confounding than observational estimates, are not consistent with a substantial effect of coffee consumption on reducing prostate cancer incidence or progression.
Comins C, Heinemann L, Harrington K, Melcher A, De Bono J, Pandha H (2008) Reovirus: Viral therapy for cancer 'as nature intended', CLINICAL ONCOLOGY 20 (7) pp. 548-554 ELSEVIER SCIENCE LONDON
Chowdhury S, Pandha H (2006) Targeting renal cell carcinoma, CLINICAL ONCOLOGY 18 (7) pp. 511-512 ELSEVIER SCIENCE LONDON
Pandha HS, Relph K, Harrington K (2008) Treatment of Cancer
5th Edition
Chapter Gene Therapy,
5th Edition
Chapter Gene Therapy,
Bonilla C, Lewis SJ, Rowlands M-A, Gaunt TR, Smith GD, Gunnell D, Palmer T, Donovan JL, Hamdy FC, Neal DE, Eeles R, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Wiklund F, Groenberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Pashayan N, Khaw K-T, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha H, Lathrop M, Martin RM, Holly JMP (2016) Assessing the role of insulin-like growth factors and binding proteins in prostate cancer using Mendelian randomization: Genetic variants as instruments for circulating levels, INTERNATIONAL JOURNAL OF CANCER 139 (7) pp. 1520-1533 WILEY-BLACKWELL
Appleton ES, Turnbull S, Ralph C, West E, Scott K, Harrington K, Pandha H, Melcher A (2015) Talimogene laherparepvec in the treatment of melanoma, EXPERT OPINION ON BIOLOGICAL THERAPY 15 (10) pp. 1517-1530 TAYLOR & FRANCIS LTD
Daniels TR, Neacato II, Rodriguez JA, Pandha HS, Morgan R, Penichet ML (2014) TARGETING THE HOX TRANSCRIPTION FACTORS AND CD71 IN MULTIPLE MYELOMA, ANTICANCER RESEARCH 34 (10) pp. 6107-6108 INT INST ANTICANCER RESEARCH
Karapanagiotou EM, Roulstone V, Twigger K, Ball M, Tanay M, Nutting C, Newbold K, Gore ME, Larkin J, Syrigos KN, Coffey M, Thompson B, Mettinger K, Vile RG, Pandha HS, Hall GD, Melcher AA, Chester J, Harrington KJ (2012) Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies., Clin Cancer Res 18 (7) pp. 2080-2089
PURPOSE: Reovirus type 3 Dearing (RT3D) replicates preferentially in Ras-activated cancers. RT3D shows synergistic in vitro cytotoxicity in combination with platins and taxanes. The purpose of this phase I/II study was to assess RT3D combined with carboplatin/paclitaxel in patients with advanced cancers. EXPERIMENTAL DESIGN: Patients were initially treated in a dose-escalating, phase I trial with intravenous RT3D days 1 to 5, carboplatin [area under curve (AUC) 5, day 1] and paclitaxel (175 mg/m(2), day 1) 3-weekly. RT3D was escalated through three dose levels: 3 × 10(9), 1 × 10(10), and 3 × 10(10) TCID(50) in cohorts of three. Primary endpoints were to define the maximum tolerated dose and dose-limiting toxicity and to recommend a dose for phase II studies. Secondary endpoints included pharmacokinetics, immune response, and antitumor activity. A subsequent phase II study using the 3 × 10(10) TCID(50) dose characterized the response rate in patients with head and neck cancer. RESULTS: Thirty-one heavily pretreated patients received study therapy. There were no dose-limiting toxicities during dose-escalation and most toxicities were grade I/II. Overall effectiveness rates were as follows: one patient had a complete response (3.8%), six patients (23.1%) had partial response, two patients (7.6%) had major clinical responses clinically evaluated in radiation pretreated lesions which are not evaluable by Response Evaluation Criteria in Solid Tumors (RECIST), nine patients (34.6%) had stable disease, and eight patients (30.8%) had disease progression. Viral shedding was minimal and antiviral immune responses were attenuated compared with previous single-agent data for RT3D. CONCLUSIONS: The combination of RT3D plus carboplatin/paclitaxel is well tolerated with evidence of activity in cancer of the head and neck. A randomized phase III study is currently open for recruitment.
Dalgleish A, Pandha H (2007) Tumor antigens as surrogate markers and targets for therapy and vaccines, ADVANCES IN CANCER RESEARCH, VOL 96 96 pp. 175-190 ELSEVIER ACADEMIC PRESS INC
Killick E, Morgan R, Launchbury F, Annels NE, Bancroft E, Page E, Castro E, Kote-Jarai Z, Eeles RA, Pandha HS (2012) Detecting prostate cancer in BRCA1 and BRCA2 mutation carriers: A role for EN2?, JOURNAL OF CLINICAL ONCOLOGY 30 (15) AMER SOC CLINICAL ONCOLOGY
Szulkin R, Karlsson R, Whitington T, Aly M, Gronberg H, Eeles RA, Easton DF, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, FitzGerald LM, Henderson BE, Schumacher FR, Haiman CA, Sipeky C, Tammela TLJ, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah PDP, Pashayan N, Khaw K-T, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubinski J, Kluzniak W, Cannon-Albright L, Brenner H, Herrmann V, Holleczek B, Park JY, Sellers TA, Lim H-Y, Slavov C, Kaneva RP, Mitev VI, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Batra J, Clements JA, Albanes D, Andriole GL, Berndt SI, Chanock S, Gapstur SM, Giovannucci EL, Hunter DJ, Kraft P, Le Marchand L, Ma J, Mondul AM, Penney KL, Stampfer MJ, Stevens VL, Weinstein SJ, Trichopoulou A, Bueno-de-Mesquita BH, Tjonneland A, Cox DG, Maehle L, Schleutker J, Lindstroem S, Wiklund F (2015) Genome-Wide Association Study of Prostate Cancer-Specific Survival, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION 24 (11) pp. 1796-1800 AMER ASSOC CANCER RESEARCH
Pandha H, Birchall L, Meyer B, Wilson N, Relph K, Anderson C, Harrington K (2006) Antitumor effects of aminobisphosphonates on renal cell carcinoma cell lines, JOURNAL OF UROLOGY 176 (5) pp. 2255-2261 ELSEVIER SCIENCE INC
Donnelly O, Vile R, Pandha H, Harrington K, Melcher A (2012) The hitchhiker's guide to virotherapy., Oncotarget 3 (8) pp. 735-736
Morgan R, Boxall A, Harrington KJ, Simpson GR, Michael A, Pandha HS (2014) Targeting HOX transcription factors in prostate cancer., BMC Urol 14
BACKGROUND: The HOX genes are a family of transcription factors that help to determine cell and tissue identity during early development, and which are also over-expressed in a number of malignancies where they have been shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor of HOX function. METHODS: HOX function was inhibited using the HXR9 peptide. HOX gene expression was assessed by RNA extraction from cells or tissues followed by quantitative PCR, and siRNA was used to block the expression of the HOX target gene, cFos. In vivo modelling involved a mouse flank tumour induced by inoculation with LNCaP cells. RESULTS: In this study we show that the expression of HOX genes in prostate tumours is greatly increased with respect to normal prostate tissue. Targeting the interaction between HOX proteins and their PBX cofactor induces apoptosis in the prostate cancer derived cell lines PC3, DU145 and LNCaP, through a mechanism that involves a rapid increase in the expression of cFos, an oncogenic transcription factor. Furthermore, disrupting HOX/PBX binding using the HXR9 antagonist blocks the growth of LNCaP tumours in a xenograft model over an extended period. CONCLUSION: Many HOX genes are highly over-expressed in prostate cancer, and prostate cancer cells are sensitive to killing by HXR9 both in vitro and in vivo. The HOX genes are therefore a potential therapeutic target in prostate cancer.
Harrington KJ, Vile RG, Melcher A, Chester J, Pandha HS (2010) Clinical trials with oncolytic reovirus: Moving beyond phase I into combinations with standard therapeutics, CYTOKINE & GROWTH FACTOR REVIEWS 21 (2-3) pp. 91-98 ELSEVIER SCI LTD
Morgan R, Boxall A, Bhatt A, Bailey M, Hindley R, Langley S, Whitaker HC, Neal DE, Ismail M, Whitaker H, Annels N, Michael A, Pandha H (2011) Engrailed-2 (EN2): A Tumor Specific Urinary Biomarker for the Early Diagnosis of Prostate Cancer, CLINICAL CANCER RESEARCH 17 (5) pp. 1090-1098 AMER ASSOC CANCER RESEARCH
Comins C, Spicer J, Protheroe A, Mukherji D, Coffey M, Thompson B, Harrington K, Pandha H (2008) A Phase I Study to Evaluate Systemic Wild-type Reovirus (REOLYSIN)(R) in Combination With Docetaxel in Patients With Advanced Malignancies, JOURNAL OF IMMUNOTHERAPY 31 (9) pp. 951-951 LIPPINCOTT WILLIAMS & WILKINS
Michael A, Plowright L, Boxall A, Bhatt A, Di Palma S, Parker C, Pandha H (2010) Evaluation of EN2 as a urine-based biomarker for prostate cancer., J Clin Oncol 28, 2010 (suppl; abstr e15129)
Background: Prostate cancer is a leading cause of cancer related death in men but its diagnosis is still complicated by the lack of a highly predictive biochemical marker. Here we show that the transcription factor Engrailed-2 is secreted from prostate tumours in a highly specific manner and is present in the urine of men with prostate cancer. Methods: Urine was collected under standardised conditions from men with prostate cancer, or with non-cancerous conditions of the prostate such as benign prostatic hypertrophy, or men who were found to have no prostate abnormalities after saturation biopsy. Results: Engrailed-2 protein was detected in the untreated, unconcentrated urine of 62% of men with prostate cancer, but only 3% of men with no prostatic abnormalities (n=258, p
Morgan R, Fairfax B, Pandha HS (2006) Calcium insensitivity of FA-6, a cell line derived from a pancreatic cancer associated with humoral hypercalcemia, is mediated by the significantly reduced expression of the Calcium Sensitive Receptor transduction component p38 MAPK, MOLECULAR CANCER 5 ARTN 51 BIOMED CENTRAL LTD
Jebar A, West E, Scott K, Thomson S, Corns R, Coffey MC, Rose A, Nuovo G, Ryan M, Errington-Mais F, Ralph C, Twelves C, Griffin S, Harrington KJ, Pandha HS, Donnely O, Selby PJ, Vile R, Short S, Melcher A (2014) Oncolytic wild-type reovirus infection in brain tumors following intravenous administration in patients., JOURNAL OF CLINICAL ONCOLOGY 32 (15) AMER SOC CLINICAL ONCOLOGY
Errington F, Steele L, Prestwich R, Harrington KJ, Pandha HS, Vidal L, de Bono J, Selby P, Coffey M, Vile R, Melcher A (2008) Reovirus activates human dendritic cells to promote innate antitumor immunity, JOURNAL OF IMMUNOLOGY 180 (9) pp. 6018-6026 AMER ASSOC IMMUNOLOGISTS
Kelly Z, Pandha H, Madhuri K, Morgan R, Michael A (2012) HOX GENE EXPRESSION IN OVARIAN CANCER, ANNALS OF ONCOLOGY 23 pp. 68-68 OXFORD UNIV PRESS
Enting D, Iannitto ML, Binda E, Eberl M, Pandha H, Hayday A (2013) Effects of concomitant therapies on gd T cell responses to zoledronate in patients with advanced prostate cancer, IMMUNOLOGY 140 pp. 69-69 WILEY-BLACKWELL
Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, Rommelfanger D, Ilett E, Pease L, Pandha H, Harrington K, Selby P, Melcher A, Vile R (2012) Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma, Nature Biotechnology 30 (4) pp. 337-343
Multiple intravenous injections of a cDNA library, derived from human melanoma cell lines and expressed using the highly immunogenic vector vesicular stomatitis virus (VSV), cured mice with established melanoma tumors. Successful tumor eradication was associated with the ability of mouse lymphoid cells to mount a tumor-specific CD4 + interleukin (IL)-17 recall response in vitro. We used this characteristic IL-17 response to screen the VSV-cDNA library and identified three different VSV-cDNA virus clones that, when used in combination but not alone, achieved the same efficacy against tumors as the complete parental virus library. VSV-expressed cDNA libraries can therefore be used to identify tumor rejection antigens that can cooperate to induce anti-tumor responses. This technology should be applicable to antigen discovery for other cancers, as well as for other diseases in which immune reactivity against more than one target antigen contributes to disease pathology. © 2012 Nature America, Inc. All rights reserved.
Ilett E, Kottke T, Donnelly O, Thompson J, Willmon C, Diaz R, Zaidi S, Coffey M, Selby P, Harrington K, Pandha H, Melcher A, Vile R (2014) Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus., Mol Ther 22 (10) pp. 1851-1863
Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells--but not from plasma--suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b(+) cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well-established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic.
Kottke T, Boisgerault N, Pulido J, Vile R, Diaz RM, Rommelfanger-Konkol D, Thompson J, Donnelly O, Melcher A, Selby P, Mukhopadhyay D, Kaspar R, Coffey M, Pandha H, Harrington K (2013) Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence, Nature Medicine
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment.
Roulstone V, Pedersen M, Kyula J, Mansfield D, Khan AA, Mcentee G, Wilkinson M, Karapanagiotou E, Coffey M, Marais R, Jebar A, Errington-Mais F, Melcher A, Vile R, Pandha H, Mclaughlin M, Harrington KJ (2015) BRAF-and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress, Molecular Therapy 23 (5) pp. 931-942
© 2015 The American Society of Gene & Cell Therapy.Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID 50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma).
Harris D, Vidal L, Melcher A, Newbold K, Anthony A, Karavasilis V, Agarwal R, White C, Twigger K, Coffey M, Mettinger K, Thompson B, Pandha H, De-Bono J, Harrington K (2007) A Phase I study to evaluate the feasibility, safety and biological effects of intratumoural administration of wild-type Reovirus (REOLYSIN (R)) in combination with radiation in patients with advanced malignancies., MOLECULAR CANCER THERAPEUTICS 6 (12) pp. 3458S-3458S AMER ASSOC CANCER RESEARCH
Khankari NK, Murff HJ, Zeng C, Wen W, Eeles RA, Easton DF, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Donovan JL, Pashayan N, Khaw K-T, Stanford JL, Blot WJ, Thibodeau SN, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha H, Zheng W (2016) Polyunsaturated fatty acids and prostate cancer risk: a Mendelian randomisation analysis from the PRACTICAL consortium, BRITISH JOURNAL OF CANCER 115 (5) pp. 624-631 NATURE PUBLISHING GROUP
McGrath SE, Michael A, Morgan R, Pandha H (2013) EN2: a novel prostate cancer biomarker., Biomark Med 7 (6) pp. 893-901
Extensive efforts to identify a clinically useful biomarker for the diagnosis of prostate cancer have resulted in important insights into the biology of the disease, but no new test has been approved by regulatory authorities. The unmet need has also shifted to identifying biomarkers that not only diagnose prostate cancer but also indicate whether the patient has 'significant' disease. EN2 is a homeobox-containing transcription factor secreted specifically by prostate cancers into urine, where it can be detected by a simple ELISA assay. A number of studies have demonstrated the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, cheap and efficient prostate cancer biomarker.
Daniels TR, Neacato II, Rodriguez JA, Pandha HS, Morgan R, Penichet ML (2010) Disruption of HOX activity leads to cell death that can be enhanced by the interference of iron uptake in malignant B cells, LEUKEMIA 24 (9) pp. 1555-1565 NATURE PUBLISHING GROUP
de Bono JS, Piulats JM, Pandha HS, Petrylak DP, Saad F, Aparicio LM, Sandhu SK, Fong P, Gillessen S, Hudes GR, Wang T, Scranton J, Pollak MN (2014) Phase II randomized study of figitumumab plus docetaxel and docetaxel alone with crossover for metastatic castration-resistant prostate cancer., Clin Cancer Res 20 (7) pp. 1925-1934
PURPOSE: Figitumumab is a human IgG2 monoclonal antibody targeting insulin-like growth factor 1 receptor (IGF-1R), with antitumor activity in prostate cancer. This phase II trial randomized chemotherapy-naïve men with progressing castration-resistant prostate cancer to receive figitumumab every 3 weeks with docetaxel/prednisone (Arm A) or docetaxel/prednisone alone (Arm B1). At progression on Arm B1, patients could cross over to the combination (Arm B2). EXPERIMENTAL DESIGN: Prostate-specific antigen (PSA) response was the primary endpoint; response assessment on the two arms was noncomparative and tested separately; H0 = 0.45 versus HA = 0.60 (± = 0.05; ² = 0.09) for Arm A; H0 = 0.05 versus HA = 0.20 (± = 0.05, ² = 0.10) for Arm B2. A comparison of progression-free survival (PFS) on Arms A and B1 was planned. RESULTS: A total of 204 patients were randomized and 199 treated (Arm A: 97; Arm B1: 102); 37 patients crossed over to Arm B2 (median number of cycles started: Arm A = 8; B1 = 8; B2 = 4). PSA responses occurred in 52% and 60% of Arms A and B1, respectively; the primary PSA response objective in Arm A was not met. Median PFS was 4.9 and 7.9 months, respectively (HR = 1.44; 95% confidence interval, 1.06-1.96). PSA response rate was 28% in Arm B2. The figitumumab combination appeared more toxic, with more treatment-related grade 3/4 adverse events (75% vs. 56%), particularly hyperglycemia, diarrhea, and asthenia, as well as treatment-related serious adverse events (41% vs. 15%), and all-causality grade 5 adverse events (18% vs. 8%). CONCLUSION: IGF-1R targeting may merit further evaluation in this disease in selected populations, but combination with docetaxel is not recommended.
Comins C, Spicer J, Protheroe A, Roulstone V, Twigger K, White CM, Vile R, Melcher A, Coffey MC, Mettinger KL, Nuovo G, Cohn DE, Phelps M, Harrington KJ, Pandha HS (2010) REO-10: A Phase I Study of Intravenous Reovirus and Docetaxel in Patients with Advanced Cancer, CLINICAL CANCER RESEARCH 16 (22) pp. 5564-5572 AMER ASSOC CANCER RESEARCH
Simpson GR, Horvath A, Annels NE, Pencavel T, Metcalf S, Seth R, Peschard P, Price T, Coffin RS, Mostafid H, Melcher AA, Harrington KJ, Pandha HS (2012) Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer, BRITISH JOURNAL OF CANCER 106 (3) pp. 496-507
Pulido J, Kottke T, Thompson J, Galivo F, Wongthida P, Diaz RM, Rommelfanger D, Ilett E, Pease L, Pandha H, Harrington K, Selby P, Melcher A, Vile R (2012) Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma, NATURE BIOTECHNOLOGY 30 (4) pp. 336-343 NATURE PUBLISHING GROUP
Hingorani M, White CL, Zaidi S, Merron A, Peerlinck I, Gore ME, Nutting CM, Pandha HS, Melcher AA, Vile RG, Vassaux G, Harrington KJ (2008) Radiation-mediated up-regulation of gene expression from replication-defective adenoviral vectors: Implications for sodium iodide symporter gene therapy, CLINICAL CANCER RESEARCH 14 (15) pp. 4915-4924 AMER ASSOC CANCER RESEARCH
Balls G, Quatan N, Michael A, Lancashire L, Adams V, Hoffman B, Pfirschke C, Russell N, Whelan M, Pandha H (2007) Immunological response patterns correlate with clinical outcome after allogeneic vaccination in hormone resistant prostate cancer metastatic to bone, JOURNAL OF IMMUNOTHERAPY 30 (8) pp. 891-891 LIPPINCOTT WILLIAMS & WILKINS
Kottke T, Boisgerault N, Diaz RM, Donnelly O, Rommelfanger-Konkol D, Pulido J, Thompson J, Mukhopadhyay D, Kaspar R, Coffey M, Pandha H, Melcher A, Harrington K, Selby P, Vile R (2013) Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence, Nature Medicine 19 (12) pp. 1625-1631
Tumor recurrence represents a major clinical challenge. Our data show that emergent recurrent tumors acquire a phenotype radically different from that of their originating primary tumors. This phenotype allows them to evade a host-derived innate immune response elicited by the progression from minimal residual disease (MRD) to actively growing recurrence. Screening for this innate response predicted accurately in which mice recurrence would occur. Premature induction of recurrence resensitized MRD to the primary therapy, suggesting a possible paradigm shift for clinical treatment of dormant disease in which the current expectant approach is replaced with active attempts to uncover MRD before evolution of the escape phenotype is complete. By combining screening with second-line treatments targeting innate insensitivity, up to 100% of mice that would have otherwise relapsed were cured. These data may open new avenues for early detection and appropriately timed, highly targeted treatment of tumor recurrence irrespective of tumor type or frontline treatment. © 2013 Nature America, Inc.
Ilett EJ, Prestwich RJ, Kottke T, Errington F, Thompson JM, Harrington KJ, Pandha HS, Coffey M, Selby PJ, Vile RG, Melcher AA (2009) Dendritic cells and T cells deliver oncolytic reovirus for tumour killing despite pre-existing anti-viral immunity, GENE THERAPY 16 (5) pp. 689-699 NATURE PUBLISHING GROUP
Horvath A, Simpson GR, Coffin RS, Mostafid H, Pandha H (2009) NOVEL INTRAVESICAL THERAPY FOR NON MUSCLE INVASIVE BLADDER CANCER: COMBINATION OF A FUSOGENIC GLYCOPROTEIN, PRO-DRUG ACTIVATION AND ONCOLYTIC HERPES SIMPLEX VIRUS, EUR UROL SUPPL 8 (4) pp. 196-196 ELSEVIER SCIENCE BV
Prestwich RJ, Errington F, Ilett EJ, Morgan RSM, Scott KJ, Kottke T, Thompson J, Morrison EE, Harrington KJ, Pandha HS, Selby PJ, Vile RG, Melcher AA (2008) Tumor Infection by Oncolytic Reovirus Primes Adaptive Antitumor Immunity, CLINICAL CANCER RESEARCH 14 (22) pp. 7358-7366 AMER ASSOC CANCER RESEARCH
Gabitass RF, Annels NE, Crawshaw J, Pandha HS, Middleton GW (2011) Use of gemcitabine- (Gem) and fluropyrimidine (FP)-based chemotherapy to reduce myeloid-derived suppressor cells (MDSCs) in pancreatic (PC) and esophagogastric cancer (EGC)., JOURNAL OF CLINICAL ONCOLOGY 29 (15) AMER SOC CLINICAL ONCOLOGY
Ilett E, Kottke T, Donnelly O, Thompson J, Willmon C, Diaz R, Zaidi S, Coffey M, Selby P, Harrington K, Pandha H, Melcher A, Vile R (2014) Cytokine conditioning enhances systemic delivery and therapy of an oncolytic virus, Molecular Therapy 22 (10) pp. 1851-1863
© The American Society of Gene & Cell Therapy.Optimum clinical protocols require systemic delivery of oncolytic viruses in the presence of an intact immune system. We show that preconditioning with immune modulators, or loading virus onto carrier cells ex vivo, enhances virus-mediated antitumor activity. Our early trials of systemic reovirus delivery showed that after infusion reovirus could be recovered from blood cells - but not from plasma - suggesting that rapid association with blood cells may protect virus from neutralizing antibody. We therefore postulated that stimulation of potential carrier cells directly in vivo before intravenous viral delivery would enhance delivery of cell-associated virus to tumor. We show that mobilization of the CD11b + cell compartment by granulocyte macrophage-colony stimulating factor immediately before intravenous reovirus, eliminated detectable tumor in mice with small B16 melanomas, and achieved highly significant therapy in mice bearing well-established tumors. Unexpectedly, cytokine conditioning therapy was most effective in the presence of preexisting neutralizing antibody. Consistent with this, reovirus bound by neutralizing antibody effectively accessed monocytes/macrophages and was handed off to tumor cells. Thus, preconditioning with cytokine stimulated recipient cells in vivo for enhanced viral delivery to tumors. Moreover, preexisting neutralizing antibody to an oncolytic virus may, therefore, even be exploited for systemic delivery to tumors in the clinic.
Gabitass RF, Annels NE, Pandha HS, Middleton AW (2010) Prevalence and prognostic significance of myeloid-derived suppressor cells and regulatory T cells in pancreatic and esophagogastric cancer, JOURNAL OF CLINICAL ONCOLOGY 28 (15) AMER SOC CLINICAL ONCOLOGY
Agrawal VK, Copeland KM, Barbachano Y, Rahim A, Seth R, White CL, Hingorani M, Nutting CM, Kelly M, Harris P, Pandha H, Melcher AA, Vile RG, Porter C, Harrington KJ (2009) Microvascular free tissue transfer for gene delivery: in vivo evaluation of different routes of plasmid and adenoviral delivery, GENE THERAPY 16 (1) pp. 78-92 NATURE PUBLISHING GROUP
Karapanagiotou E, Pandha H, Hall G, Chester J, Melcher A, De Bono J, Gore M, Nutting C, Harrington K (2008) Phase I Trial of Oncolytic Reovirus (Reolysin) in Combination With Carboplatin/Paclitaxel in Patients With Advanced Solid Cancers, JOURNAL OF IMMUNOTHERAPY 31 (9) pp. 952-952 LIPPINCOTT WILLIAMS & WILKINS
Zaidi S, Blanchard M, Shim K, Ilett E, Kottke T, Thompson J, Celis E, Pandha H, Selby P, Melcher A, Harrington K, Vile R (2014) Acquisition of Mutated BRAF Is as a Major Effector of Melanoma Recurrence Which Can Be Targeted By Immuno- or Chemo-Therapy, MOLECULAR THERAPY 22 pp. S245-S245 NATURE PUBLISHING GROUP
Papaetis GS, Karapanagiotou LM, Pandha H, Syrigos KN (2008) Targeted therapy for advanced renal cell cancer: Cytokines and beyond, CURRENT PHARMACEUTICAL DESIGN 14 (22) pp. 2229-2251 BENTHAM SCIENCE PUBL LTD
Morgan R, Gray S, Gillett C, Tabi Z, Launchbury F, Spicer J, Harrington K, Pandha HS (2014) HOX TRANSCRIPTION FACTORS ARE POTENTIAL TARGETS AND MARKERS IN MALIGNANT MESOTHELIOMA, ANTICANCER RESEARCH 34 (10) pp. 6069-6071 INT INST ANTICANCER RESEARCH
Roberts A, Serrano M, Binda E, Vantourout P, Pandha H, Hayday AC (2010) Expansion of Autologous Human V gamma 9V delta 2 T Cells Ex Vivo: Potential for Adoptive T Cell Therapy of Prostate Cancer, J IMMUNOTHER 33 (8) pp. 864-864 LIPPINCOTT WILLIAMS & WILKINS
Kyula JN, Khan AA, Mansfield D, Karapanagiotou EM, Mclaughlin M, Roulstone V, Zaidi S, Pencavel T, Touchefeu Y, Seth R, Chen NG, Yu YA, Zhang Q, Melcher AA, Vile RG, Pandha HS, Ajaz M, Szalay AA, Harrington KJ (2014) Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-± signaling, Oncogene 33 (13) pp. 1700-1712
Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of-concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV-1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in V600D BRAF/V600E mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in V600D BRAF/V600E BRAF mutant cell lines and this was associated with TNF-± secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-± secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation inV600D/E BRAF mutant tumors. © 2014 Macmillan Publishers Limited.
Mansfield D, Pencavel T, Kyula JN, Zaidi S, Roulstone V, Thway K, Karapanagiotou L, Khan AA, McLaughlin M, Touchefeu Y, Seth R, Melcher AA, Vile RG, Pandha HS, Harrington KJ (2013) Oncolytic Vaccinia virus and radiotherapy in head and neck cancer, Oral Oncology 49 (2) pp. 108-118
Objective: Oncolytic forms of attenuated Vaccinia virus are now in clinical development, assessing the compatibility of this novel treatment with radiotherapy may reveal exploitable synergistic relationships. Materials and methods: In vitro analyses of cell killing, cell cycle effects and caspase activation were carried out on HN3, HN5, CAL27, Detroit, SIHN5B, and PJ41 cells. In vivo studies of the virus and X-radiation were performed on H&N xenografts in CD1 nude mice. Results: Cell killing in vitro was demonstrated to be dose- and time-dependent. Infection causes an increase in S-phase and sub-G1 cells. A dose dependent increase in active caspase-3 indicated induction of apoptosis. Xenografts injected with Vaccinia stabilised and frequently completely regressed. Combination with radiation generated additional cell death, induction of caspase activity and in vivo further improved long term regression rates. Conclusions: These data support continued exploration of this therapy combination and indicates potential for clinical trials in head and neck cancer. © 2012 Elsevier Ltd. All rights reserved.
Donnelly O, Harrington K, Melcher A, Pandha H (2013) Live viruses to treat cancer., J R Soc Med 106 (8) pp. 310-314
Viruses that selectively replicate in cancer cells, leading to the death of the cell, are being studied for their potential as cancer therapies. Some of these viruses are naturally occurring but cause little if any illness in humans; others have been engineered to make them specifically able to kill cancer cells while sparing normal cells. These oncolytic viruses may be selective for cancer cells because viral receptors are over-expressed on the surface of cancer cells or because antiviral pathways are distorted in cancer cells. Additionally, when oncolytic viruses kill cancer cells, it can stimulate an antitumour immune response from the host that can enhance efficacy. Numerous early phase trials of at least six oncolytic viruses have been reported with no evidence of concerning toxicity either as single agents or in combination with chemotherapies and radiotherapy. Three oncolytic viruses have reached randomized testing in cancer patients; reolysin in head and neck cancer and JX594 in hepatocellular cancers, while results from the first-phase III trial of T-vec in metastatic melanoma are expected shortly.
Havranek EG, Labarthe M-C, Ward S, Anderson CJ, Whelan MA, Pandha H (2008) A novel murine model of allogeneic vaccination against renal cancer, BJU INTERNATIONAL 101 (9) pp. 1165-1169 BLACKWELL PUBLISHING
Anesti A-M, Simpson GR, Price T, Pandha HS, Coffin RS (2010) Expression of RNA interference triggers from an oncolytic herpes simplex virus results in specific silencing in tumour cells in vitro and tumours in vivo, BMC CANCER 10 ARTN 486 BIOMED CENTRAL LTD
Donnelly OG, Errington-Mais F, Steele L, Hadac E, Jennings V, Scott K, Peach H, Phillips RM, Bond J, Pandha H, Harrington K, Vile R, Russell S, Selby P, Melcher AA (2011) Measles virus causes immunogenic cell death in human melanoma., Gene Ther
Oncolytic viruses (OV) are promising treatments for cancer, with several currently undergoing testing in randomised clinical trials. Measles virus (MV) has not yet been tested in models of human melanoma. This study demonstrates the efficacy of MV against human melanoma. It is increasingly recognised that an essential component of therapy with OV is the recruitment of host antitumour immune responses, both innate and adaptive. MV-mediated melanoma cell death is an inflammatory process, causing the release of inflammatory cytokines including type-1 interferons and the potent danger signal HMGB1. Here, using human in vitro models, we demonstrate that MV enhances innate antitumour activity, and that MV-mediated melanoma cell death is capable of stimulating a melanoma-specific adaptive immune response.Gene Therapy advance online publication, 15 December 2011; doi:10.1038/gt.2011.205.
Saunders EJ, Dadaev T, Leongamornlert DA, Olama AA, Benlloch S, Giles GG, Wiklund F, Grönberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Pasayan N, Khaw KT, Stanford JL, Blot WJ, Thibodeau SN, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park JY, Kaneva R, Batra J, Teixeira MR, Pandha H, Govindasami K, Muir K, UK Genetic Prostate Cancer Study Collaborators, UK ProtecT Study Collaborators, PRACTICAL Consortium, Easton DF, Eeles RA, Kote-Jarai Z (2016) Gene and pathway level analyses of germline DNA-repair gene variants and prostate cancer susceptibility using the iCOGS-genotyping array., British Journal of Cancer 114 pp. 945-952 Cancer Research UK
BACKGROUND: Germline mutations within DNA-repair genes are implicated in susceptibility to multiple forms of cancer. For prostate cancer (PrCa), rare mutations in BRCA2 and BRCA1 give rise to moderately elevated risk, whereas two of
Gusev A, Shi H, Kichaev G, Pomerantz M, Li F, Long HW, Ingles SA, Kittles RA, Strom SS, Rybicki BA, Nemesure B, Isaacs WB, Zheng W, Pettaway CA, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, John EM, Murphy AB, Signorello LB, Carpten J, Leske MC, Wu S-Y, Hennis AJM, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Witte JS, Casey G, Kaggwa S, Cook MB, Stram DO, Blot WJ, Eeles RA, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Gronberg H, Wiklund F, Aly M, Henderson BE, Schleutker J, Wahlfors T, Tammela TLJ, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw K-T, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Wokolorczyk D, Kluzniak W, Cannon-Albright L, Teerlink C, Brenner H, Dieffenbach AK, Arndt V, Park JY, Sellers TA, Lin H-Y, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements JA, Teixeira MR, Pandha HS, Michael A, Paulo P, Maia S, Kierzek A, Conti DV, Albanes D, Berg C, Berndt SI, Campa D, Crawford ED, Diver WR, Gapstur SM, Gaziano JM, Giovannucci E, Hoover R, Hunter DJ, Johansson M, Kraft P, Le Marchand L, Lindstrom S, Navarro C, Overvad K, Riboli E, Siddiq A, Stevens VL, Trichopoulos D, Vineis P, Yeager M, Trynka G, Raychaudhuri S, Schumacher FR, Price AL, Freedman ML, Haiman CA, Pasaniuc B, Cook M, Guy M, Govindasami K, Leongamornlert D, Sawyer EJ, Wilkinson R, Saunders EJ, Tymrakiewicz M, Dadaev T, Morgan A, Fischer C, Hazel S, Livni N, Lophatananon A, Pedersen J, Hopper JL, Adolfson J, Stattin P, Johansson J-E, Cavalli-Bjoerkman C, Karlsson A, Broms M, Auvinen A, Kujala P, Maeaettaenen L, Murtola T, Taari K, Weischer M, Nielsen SF, Klarskov P, Roder A, Iversen P, Wallinder H, Signorello LB, Blot WJ, Tillmans L, Riska S, Wang L, Rinckleb A, Lubiski J, Stegmaier C, Pow-Sang J, Park H, Radlein S, Rincon M, Haley J, Zachariah B, Kachakova D, Popov E, Mitkova A, Vlahova A, Dikov T, Christova S, Heathcote P, Wood G, Malone G, Saunders K, Eckert A, Yeadon T, Kerr K, Collins A, Turner M, Srinivasan S, Kedda M-A, Alexander K, Omara T, Wu H, Henrique R, Pinto P, Santos J, Barros-Silva J (2016) Atlas of prostate cancer heritability in European and African-American men pinpoints tissue-specific regulation, Nature Communications 7
Although genome-wide association studies have identified over 100 risk loci that explain
Pandha H, Melcher A, Harrington K, Vile R (2009) Oncolytic Viruses: Time to Compare, Contrast, and Combine?, MOLECULAR THERAPY 17 (6) pp. 934-935 NATURE PUBLISHING GROUP
Annels NE, Pandha H (2013) Immunotherapy, In: Prostate Cancer: A Comprehensive Perspective pp. 925-934
© 2013 Springer-Verlag London. All rights are reserved.The approval in April 2010 by the FDA in the USA of a prostate cancer vaccine (Sipuleucel-T, Provenge, Dendreon Inc.) may herald a new era in T-cell-directed cancer therapies. The magnitude of scientific effort to reach this point should not be underestimated. The key has been unraveling the complex mechanisms between the recognition of tumor antigen, breaking immune tolerance, and generation of a long-lasting and clinically meaningful cellular response. Therapeutic vaccines (i.e., vaccines for patients with ongoing disease) have two objectives: priming Ag-specific T cells and reprogramming memory T cells (i.e., a transformation from one type of immunity to another, for example, regulatory to cytotoxic). Numerous therapeutic approaches have been tested in prostate cancer patients, including autologous and allogeneic tumor cells modified to express various cytokines, peptides, proteins, and DNA vaccines. The evolution of cellular vaccines includes addressing the local immunosuppressive tumor microenvironment, modulating immune response through checkpoint blockade and, importantly, combining cellular immunotherapy with other treatment modalities such as chemotherapy exploiting their intrinsic immunomodulatory properties.
Ismail M, Ahmed S, Laing R, Nigam R, Langley S, Pandha H, Davies J (2007) Antibody immunity to prostate cancer specific antigen in the serum of patients having cryotherapy or brachytherapy treatment compared to healthy volunteers, BJU INTERNATIONAL 99 pp. 47-48 BLACKWELL PUBLISHING
Vidal L, Pandha H, Harrington K, Fong P, Shaw H, Barrett M, Leader D, White C, Twigger K, Coffey M, Thompson B, Kaye S, De-Bono J (2005) A phase I study of a wild-type reovirus (Reolysin) given intravenously to patients with advanced malignancies., CLINICAL CANCER RESEARCH 11 (24) pp. 9106S-9107S AMER ASSOC CANCER RESEARCH
Metcalf S, Pandha HS, Morgan R (2011) Antiangiogenic effects of zoledronate on cancer neovasculature., Future Oncol 7 (11) pp. 1325-1333
Angiogenesis, one of the hallmarks of cancer, supplies nutrients to cancerous tissues to facilitate rapid growth. Targeting cancer-associated angiogenesis is an important goal in cancer therapy and there are currently many drugs that affect tumor-associated vasculature. In this article, we will focus on the antiangiogenic effects of zoledronate (ZA), a bisphosphonate drug routinely used in the treatment of cancer-associated bone disease. This article covers the known effects of ZA throughout the clinical process. It also covers the animal models of cancer that have been treated with ZA and evaluated for angiogenes is, concluding with the current clinical data pertaining to angiogenic factors after ZA treatment.
McGrath SE, Michael A, Morgan R, Pandha H (2015) EN2 in Prostate Cancer, Advances in Clinical Chemistry
© 2015 Elsevier Inc. Despite extensive efforts to identify a clinically useful diagnostic biomarker in prostate cancer, no new test has been approved by regulatory authorities. As a result, this unmet need has shifted to biomarkers that additionally indicate presence or absence of "significant" disease. EN2 is a homeodomain-containing transcription factor secreted by prostate cancer into the urine and can be detected by enzyme-linked immunoassay. EN2 may be an ideal biomarker because normal prostate tissue and benign prostatic hypertrophic cells do not secrete EN2. This review discusses the enormous potential of EN2 to address this unmet need and provide the urologist with a simple, inexpensive, and reliable prostate cancer biomarker.
Ilett EJ, Bárcena M, Errington-Mais F, Griffin S, Harrington KJ, Pandha HS, Coffey M, Selby PJ, Limpens RW, Mommaas M, Hoeben RC, Vile RG, Melcher AA (2011) Internalization of oncolytic reovirus by human dendritic cell carriers protects the virus from neutralization., Clin Cancer Res 17 (9) pp. 2767-2776
PURPOSE: Dendritic cells (DC) may be the most effective way of delivering oncolytic viruses to patients. Reovirus, a naturally occurring oncolytic virus, is currently undergoing early clinical trials; however, intravenous delivery of the virus is hampered by pre-existing antiviral immunity. Systemic delivery via cell carriage is a novel approach currently under investigation and initial studies have indicated its feasibility by using a variety of cell types and viruses. This study addressed the efficacy of human DC to transport virus in the presence of human neutralizing serum. EXPERIMENTAL DESIGN: Following reovirus-loading, DC or T cells were cocultured with melanoma cells with or without neutralizing serum; the melanoma cells were then analyzed for cell death. Following reovirus loading, cells were examined by electron microscopy to identify mechanisms of delivery. The phagocytic function of reovirus-loaded DC was investigated by using labeled tumor cells and the ability of reovirus-loaded DC to prime T cells was also investigated. RESULTS: In the presence of human neutralizing serum DC, but not T cells, were able to deliver reovirus for melanoma cell killing in vitro. Electron microscopy suggested that DC protected the virus by internalization, whereas with T cells it remained bound to the surface and hence accessible to neutralizing antibodies. Furthermore, DC loaded with reovirus were fully functional with regard to phagocytosis and priming of specific antitumor immune responses. CONCLUSIONS: The delivery of reovirus via DC could be a promising new approach offering the possibility of combining systemic viral therapy for metastatic disease with induction of an antitumor immune response.
Rudman SM, Comins C, Mukherji D, Coffey M, Mettinger K, Protheroe A, Harrington KJ, Pandha H, Spicer JF (2009) Results of a phase I study to evaluate the feasibility, safety, and biological effects of intravenous administration of wild-type reovirus with docetaxel to patients with advanced malignancies, JOURNAL OF CLINICAL ONCOLOGY 27 (15) AMER SOC CLINICAL ONCOLOGY
Vidal L, Twigger K, White C, Coffey M, Thompson B, De-Bono J, Pandha HS, Melcher A, Kaye S, Harrington KJ (2005) Reovirus enhances radiation cytotoxicity in vitro and in vivo., CLINICAL CANCER RESEARCH 11 (24) pp. 9005S-9006S AMER ASSOC CANCER RESEARCH
Vogelzang NJ, Beer TM, Bartunkova J, Kuklk R, Miller K, Oh WK, Oudard S, Pandha HS, Sartor AO, Spisek R, Borgstein NG, Gerritsen WR (2015) Autologous dendritic cell vaccination (DCVAC/PCa) added to docetaxel chemotherapy in a double-blind, randomized phase III trial (VIABLE) in men with advanced (mCRPC) prostate cancer., JOURNAL OF CLINICAL ONCOLOGY 33 (15) AMER SOC CLINICAL ONCOLOGY
Ismail M, Morgan R, Davies J, Pandha H (2009) Inhibition of the aquaporin water channels (AQPs) increases the sensitivity of DU145 cells to cryotherapy, BJU INTERNATIONAL 103 pp. 21-21 WILEY-BLACKWELL PUBLISHING, INC
Bull CJ, Bonilla C, Holly JM, Perks CM, Davies N, Haycock P, Yu OH, Richards JB, Eeles R, Easton D, Kote-Jarai Z, Amin Al Olama A, Benlloch S, Muir K, Giles GG, MacInnis RJ, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Pashayan N, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Micheal A, Pandha H, Smith GD, Lewis SJ, Martin RM (2016) Blood lipids and prostate cancer: a Mendelian randomization analysis., Cancer medicine 5 (6) pp. 1125-1136
Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (e7 Gleason score) versus low-grade (
Twigger K, Vidal L, White CL, De Bono JS, Bhide S, Coffey M, Thompson B, Vile RG, Heinemann L, Pandha HS, Errington F, Melcher AA, Harrington KJ (2008) Enhanced in vitro and in vivo cytotoxicity of combined reovirus and radiotherapy, CLINICAL CANCER RESEARCH 14 (3) pp. 912-923 AMER ASSOC CANCER RESEARCH
Horvath A, Simpson GR, Coffin RS, Mostafid H, Pandha H (2010) NOVEL INTRAVESICAL THERAPY FOR NON MUSCLE INVASIVE BLADDER CANCER USING A GENETICALLY MODIFIED ONCOLYTIC HERPES SIMPLEX VIRUS, EUROPEAN UROLOGY SUPPLEMENTS 9 (6) pp. 646-646 ELSEVIER SCIENCE BV
Simpson GR, Horvath A, Harrington K, Coffin RS, Pandha H (2008) Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer, EJC SUPPLEMENTS 6 (12) pp. 97-98 PERGAMON-ELSEVIER SCIENCE LTD
Prestwich RJ, Ilett EJ, Errington F, Diaz RM, Steele LP, Kottke T, Thompson J, Galivo F, Harrington KJ, Pandha HS, Selby PJ, Vile RG, Melcher AA (2009) Immune-Mediated Antitumor Activity of Reovirus Is Required for Therapy and Is Independent of Direct Viral Oncolysis and Replication, CLINICAL CANCER RESEARCH 15 (13) pp. 4374-4381 AMER ASSOC CANCER RESEARCH
Karapanagiotou EM, Chester JD, Pandha HS, Gill GM, Coffey MC, Mettinger K, Harrington KJ (2010) A phase I/II study of oncolytic reovirus plus carboplatin/paclitaxel in patients with advanced solid cancers with emphasis on squamous cell carcinoma of the head and neck(SCCHN), JOURNAL OF CLINICAL ONCOLOGY 28 (15) AMER SOC CLINICAL ONCOLOGY
Jennings VA, Ilett EJ, Scott KJ, West EJ, Vile R, Pandha H, Harrington K, Young A, Hall GD, Coffey M, Selby P, Errington-Mais F, Melcher AA (2013) Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites., Int J Cancer 134 (5) pp. 1091-1101
Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus-induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine-activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNc, IL-12, IFN± and TNF±) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune-mediated tumor cell killing.
Errington F, White CL, Twigger KR, Rose A, Scott K, Steele L, Ilett LJ, Prestwich R, Pandha HS, Coffey M, Selby P, Vile R, Harrington KJ, Melcher AA (2008) Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma, GENE THERAPY 15 (18) pp. 1257-1270 NATURE PUBLISHING GROUP
Ismail M, Bokaee S, Davies J, Harrington KJ, Pandha H (2009) Inhibition of the aquaporin 3 water channel increases the sensitivity of prostate cancer cells to cryotherapy, BRITISH JOURNAL OF CANCER 100 (12) pp. 1889-1895 NATURE PUBLISHING GROUP
Bolton GC, Simpson GR, Coffey M, Harrington K, Morgan R, Annels N, Launchbury FA, Ajaz M, Pandha H (2014) Resistance to Oncolytic Reovirus is associated with high expression of Yes-Associated Protein-1 (YAP-1) in Head and Neck Cancer, HUMAN GENE THERAPY 25 (12) pp. A12-A13 MARY ANN LIEBERT, INC
Pandha HS, Harrington KJ, Vile RG (2008) Poxviruses as immunomodulatory cancer therapeutics., In: Viral Therapy of Cancer
Ismail M, Morgan R, Harrington K, Davies J, Pandha H (2010) Immunoregulatory effects of freeze injured whole tumour cells on human dendritic cells using an in vitro cryotherapy model, CRYOBIOLOGY 61 (3) pp. 268-274 ACADEMIC PRESS INC ELSEVIER SCIENCE
De Paoli M, Perco P, Muehlberger I, Lukas A, Pandha H, Morgan R, Feng GJ, Marquette C (2015) Disease map-based biomarker selection and pre-validation for bladder cancer diagnostic, BIOMARKERS 20 (5) pp. 328-337 TAYLOR & FRANCIS LTD
Plowright L, Harrington KJ, Pandha HS, Morgan R (2009) HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer), BRITISH JOURNAL OF CANCER 100 (3) pp. 470-475 NATURE PUBLISHING GROUP
Enting D, Iannitto ML, Pandha H, Chowdhury S, Hayday A (2015) Effects of Concomitant Therapies on gamma delta T Cell Responses to Zoledronate in Patients with Advanced Prostate Cancer, CLINICAL ONCOLOGY 27 (3) pp. E4-E4 ELSEVIER SCIENCE LONDON
Zaidi S, Blanchard M, Shim K, Ilett E, Rajani K, Parrish C, Boisgerault N, Kottke T, Thompson J, Celis E, Pulido J, Selby P, Pandha H, Melcher A, Harrington K, Vile R (2014) Mutated BRAF Emerges as a Major Effector of Recurrence in a Murine Melanoma Model After Treatment With Immunomodulatory Agents., Mol Ther 23 (5) pp. 845-856
We used a VSV-cDNA library to treat recurrent melanoma, identifying immunogenic antigens, allowing us to target recurrences with immunotherapy or chemotherapy. Primary B16 melanoma tumors were induced to regress by frontline therapy. Mice with recurrent tumors were treated with VSV-cDNA immunotherapy. A Th17 recall response was used to screen the VSV-cDNA library for individual viruses encoding rejection antigens, subsequently targeted using immunotherapy or chemotherapy. Recurrent tumors were effectively treated with a VSV-cDNA library using cDNA from recurrent B16 tumors. Recurrence-associated rejection antigens identified included Topoisomerase-II±, YB-1, cdc7 kinase, and BRAF. Fourteen out of 16 recurrent tumors carried BRAF mutations (595-605 region) following frontline therapy, even though the parental B16 tumors were BRAF wild type. The emergence of mutated BRAF-containing recurrences served as an excellent target for BRAF-specific immune-(VSV-BRAF), or chemo-(PLX-4720) therapies. Successful PLX-4720 therapy of recurrent tumors was associated with the development of a broad spectrum of T-cell responses. VSV-cDNA technology can be used to identify recurrence specific antigens. Emergence of mutated BRAF may be a major effector of melanoma recurrence which could serve as a target for chemo or immune therapy. This study suggests a rationale for offering patients with initially wild-type BRAF melanomas an additional biopsy to screen for mutant BRAF upon recurrence.
Prestwich RJ, Harrington KJ, Pandha HS, Vile RG, Melcher AA, Errington F (2008) Oncolytic viruses: a novel form of immunotherapy, EXPERT REVIEW OF ANTICANCER THERAPY 8 (10) pp. 1581-1588 EXPERT REVIEWS
Pandha H, D'Ambrosio C, Heenan S, Hyde N, Di Palma S, Nutting C, Relph K, Harrington K (2009) Indium-labelled Autologous Dendritic Cells Migrate to Local Lymph Nodes after Intratumoural Injection in Head and Neck Cancer Patients, CLINICAL ONCOLOGY 21 (4) pp. 363-364 ELSEVIER SCIENCE LONDON
Annels NE, Simpson GR, Bokaee S, Riley C, Denyer M, Pandha H, Morgan R (2012) Modulation of Regulatory T Cells by Targeting The NFAT-FOXP3 Protein: Protein Interaction, JOURNAL OF IMMUNOTHERAPY 35 (9) pp. 775-775 LIPPINCOTT WILLIAMS & WILKINS
Adair RA, Scott KJ, Fraser S, Errington-Mais F, Pandha H, Coffey M, Selby P, Cook GP, Vile R, Harrington KJ, Toogood G, Melcher AA (2013) Cytotoxic and immune-mediated killing of human colorectal cancer by reovirus-loaded blood and liver mononuclear cells, International Journal of Cancer 132 (10) pp. 2327-2338
Reovirus is a promising oncolytic virus, acting by both direct and immune-mediated mechanisms, although its potential may be limited by inactivation after systemic delivery. Our study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus-loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Although direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus after intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer (NK) cells within reovirus-treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a Type I interferon-dependent manner. Similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells, and this blood cell carriage has the potential to investigate both direct and innate immune-mediated therapy against human colorectal or other cancers metastatic to the liver. What's new? Reovirus can deliver a double whammy to cancer: it hunts down and destroys ras-activated tumor cells, and it can also fire up the immune system against the tumor. The immune system, however, is a fickle ally; in addition to attacking tumor cells, an efficient immune response also rids the body of reovirus, hindering therapy. This study investigated whether therapeutic reovirus could be shielded from immune assault. They showed that loading reovirus onto blood mononuclear cells provides safe transportation to target cells, in this case, colorectal tumor cells, and the reovirus-loaded immune cells themselves also launch an attack against tumor cells. Reovirus appears to be a promising new avenue for cancer treatment. Copyright © 2012 UICC.
Jennings VA, Ilett EJ, Scott KJ, West EJ, Vile R, Pandha H, Harrington K, Young A, Hall GD, Coffey M, Selby P, Errington-Mais F, Melcher AA (2014) Lymphokine-activated killer and dendritic cell carriage enhances oncolytic reovirus therapy for ovarian cancer by overcoming antibody neutralization in ascites, International Journal of Cancer 134 (5) pp. 1091-1101
Reovirus is an oncolytic virus (OV), which acts by both direct tumor cell killing and priming of antitumor immunity. A major obstacle for effective oncolytic virotherapy is effective delivery of OV to tumor cells. Ovarian cancer is often confined to the peritoneal cavity and therefore i.p. delivery of reovirus may provide the ideal locoregional delivery, avoiding systemic dissemination. However, ovarian cancer is associated with an accumulation of ascitic fluid, which may interfere with oncolytic viral therapy. Here, we investigated the effect of ascites on reovirus-induced oncolysis against primary ovarian cancer cells and ovarian cancer cell lines. In the absence of ascites, reovirus was cytotoxic against ovarian cancer cells; however, cytotoxicity was abrogated in the presence of ascitic fluid. Neutralizing antibodies (NAb) were identified as the cause of this inhibition. Loading OV onto cell carriers may facilitate virus delivery in the presence of NAb and immune cells which have their own antitumor effector activity are particularly appealing. Immature dendritic cells (iDC), Lymphokine-activated killer (LAK) cells and LAKDC cocultures were tested as potential carriers for reovirus for tumor cell killing and immune cell priming. Reovirus-loaded LAKDC, and to a lesser degree iDC, were able to: (i) protect from NAb and hand-off reovirus for tumor cell killing; (ii) induce a proinflammatory cytokine milieu (IFNÉ£, IL-12, IFN± and TNF±) and (iii) generate an innate and specific antitumor adaptive immune response. Hence, LAKDC pulsed with reovirus represent a novel, clinically practical treatment for ovarian cancer to maximise both direct and innate/adaptive immune-mediated tumor cell killing. © 2013 The Authors. Published by Wiley Periodicals, Inc. on behalf of UICC.
Michael A, Syrigos K, Pandha H (2009) Prostate cancer chemotherapy in the era of targeted therapy, PROSTATE CANCER AND PROSTATIC DISEASES 12 (1) pp. 13-16 NATURE PUBLISHING GROUP
Michael A, Riley C, Bokaee S, Denyer M, Pandha HS, Annels NE (2011) EN2: A candidate antigen for the development of targeted therapies in ovarian cancer., JOURNAL OF CLINICAL ONCOLOGY 29 (15) AMER SOC CLINICAL ONCOLOGY
Annels NE, Gabitass RF, Pandha H, Middleton GW (2010) Elevated MDSCs in Pancreatic and Esophago-gastric Cancer Patients Correlates with Poor Prognosis, J IMMUNOTHER 33 (8) pp. 897-897 LIPPINCOTT WILLIAMS & WILKINS
Bonilla C, Lewis SJ, Martin RM, Donovan JL, Hamdy FC, Neal DE, Eeles R, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Pashayan N, Khaw KT, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha H, Lathrop M, Davey Smith G, PRACTICAL consortium (2016) Pubertal development and prostate cancer risk: Mendelian randomization study in a population-based cohort., BMC Medicine 14 (1) pp. 66-76 BioMed Central
Background: Epidemiological studies have observed a positive association between an earlier age at sexual
development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational
estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined
the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in
adolescent boys in a Mendelian randomization (MR) approach.
Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with
male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with
prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the
PRACTICAL consortium (n = 43,737) as a replication sample.
Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR)
of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64?0.89). In an instrumental variable estimation of
the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between
pubertal boys of the same age) was associated with a 77 % (95 % CI, 43?91 %) reduced odds of high Gleason prostate
cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs.
localized cancer, per tertile: 0.95; 95 % CI, 0.91?1.00) and prostate cancer-specific mortality (hazard ratio amongst cases,
per tertile: 0.94; 95 % CI, 0.90?0.98), but not with disease grade.
Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially
aggressive disease.
development and prostate cancer, but markers of sexual maturation in boys are imprecise and observational
estimates are likely to suffer from a degree of uncontrolled confounding. To obtain causal estimates, we examined
the role of pubertal development in prostate cancer using genetic polymorphisms associated with Tanner stage in
adolescent boys in a Mendelian randomization (MR) approach.
Methods: We derived a weighted genetic risk score for pubertal development, combining 13 SNPs associated with
male Tanner stage. A higher score indicated a later puberty onset. We examined the association of this score with
prostate cancer risk, stage and grade in the UK-based ProtecT case-control study (n = 2,927), and used the
PRACTICAL consortium (n = 43,737) as a replication sample.
Results: In ProtecT, the puberty genetic score was inversely associated with prostate cancer grade (odds ratio (OR)
of high- vs. low-grade cancer, per tertile of the score: 0.76; 95 % CI, 0.64?0.89). In an instrumental variable estimation of
the causal OR, later physical development in adolescence (equivalent to a difference of one Tanner stage between
pubertal boys of the same age) was associated with a 77 % (95 % CI, 43?91 %) reduced odds of high Gleason prostate
cancer. In PRACTICAL, the puberty genetic score was associated with prostate cancer stage (OR of advanced vs.
localized cancer, per tertile: 0.95; 95 % CI, 0.91?1.00) and prostate cancer-specific mortality (hazard ratio amongst cases,
per tertile: 0.94; 95 % CI, 0.90?0.98), but not with disease grade.
Conclusions: Older age at sexual maturation is causally linked to a reduced risk of later prostate cancer, especially
aggressive disease.
Pandha H, Sorensen KD, Orntoft TF, Langley S, Hoyer S, Borre M, Morgan R (2012) Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer., BJU Int 110 (6 Pt B) pp. E287-E292 Wiley-Blackwell
What's known on the subject? and What does the study add? There are a lot of potential prostate cancer biomarkers being evaluated. All aim to improve on the sensitivity and specificity of PSA. EN2 was recently shown by our group to have better sensitivity and specificity than PSA. EN2 is a simple ELISA test and is not dependent on other parameters, even PSA, unlike all the other current biomarkers under evaluation. To date, no marker correlates with the amount of cancer present - the present study shows this positive correlation with EN2 in men undergoing prostatectomy. The potential utility of this work is that by knowing that the level of EN2 corresponds to the amount of cancer present, irrelevant of tumour grade and number of cancer foci, we can define an EN2 level corresponding to small cancers, which can then undergo surveillance. We are conducting a further study that is aimed at determining whether the levels of EN2 in urine can indicate 'significant' vs 'non-significant cancer' using the threshold of 0.5 mL cancer (after Epstein's work).
Michael A, Zylstra J, Pandha H (2011) The sun study-a biobank of sequential blood samples from patients with prostate cancer, BRITISH JOURNAL OF SURGERY 98 pp. 50-50 WILEY-BLACKWELL
Ismail MI, Bokaee S, Annels N, Davies J, Pandha H (2011) Predominance of CD8 T cell infiltration coincides with reciprocal reduction in regulatory T cells following prostate cryotherapy, BRITISH JOURNAL OF SURGERY 98 pp. 48-48 WILEY-BLACKWELL
Hingorani M, White CL, Merron A, Peerlinck I, Gore ME, Slade A, Scott SD, Nutting CM, Pandha HS, Melcher AA, Vile RG, Vassaux G, Harrington KJ (2008) Inhibition of Repair of Radiation-Induced DNA Damage Enhances Gene Expression from Replication-Defective Adenoviral Vectors, CANCER RESEARCH 68 (23) pp. 9771-9778 AMER ASSOC CANCER RESEARCH
Kottke T, Donnelly O, Ilett E, Thompson J, Diaz R, Coffey M, Selby P, Pandha H, Harrington K, Melcher A, Vile R (2013) In Vivo Expansion of a Recipient Population of Cell Carriers Allows for Highly Effective Systemic Delivery of Oncolytic Reovirus Even in the Presence of Neutralizing Antibody, MOLECULAR THERAPY 21 pp. S7-S7 NATURE PUBLISHING GROUP
Alharbi RA, Pettengell R, Pandha HS, Morgan R (2012) The role of HOX genes in normal hematopoiesis and acute leukemia., Leukemia 27 (5) pp. 1000-1008
The homeobox (HOX) genes are a highly conserved family of homeodomain-containing transcription factors that specify cell identity in early development and, subsequently, in a number of adult processes including hematopoiesis. The dysregulation of HOX genes is associated with a number of malignancies including acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL), where they have been shown to support the immortalization of leukemic cells both as chimeric partners in fusion genes and when overexpressed in their wild-type form. This review covers our current understanding of the role of HOX genes in normal hematopoiesis, AML and ALL, with particular emphasis on the similarities and differences of HOX function in these contexts, their hematopoietic downstream gene targets and implications for therapy.
Hall K, Scott KJ, Rose A, Desborough M, Harrington K, Pandha H, Parrish C, Vile R, Coffey M, Bowen D, Errington-Mais F, Melcher AA (2012) Reovirus-mediated cytotoxicity and enhancement of innate immune responses against acute myeloid leukemia., Biores Open Access 1 (1) pp. 3-15
Reovirus is a naturally occurring oncolytic virus that has shown preclinical efficacy in the treatment of a wide range of tumor types and has now reached phase III testing in clinical trials. The anti-cancer activity of reovirus has been attributed to both its direct oncolytic activity and the enhancement of anti-tumor immune responses. In this study, we have investigated the direct effect of reovirus on acute myeloid leukemia (AML) cells and its potential to enhance innate immune responses against AML, including the testing of primary samples from patients. Reovirus was found to replicate in and kill AML cell lines, and to reduce cell viability in primary AML samples. The pro-inflammatory cytokine interferon alpha (IFN±) and the chemokine (C-C motif) ligand 5 (known as RANTES [regulated upon activation, normal T-cell expressed, and secreted]) were also secreted from AML cells in response to virus treatment. In addition, reovirus-mediated activation of natural killer (NK) cells, within the context of peripheral blood mononuclear cells, stimulated their anti-leukemia response, with increased NK degranulation and IFN³ production and enhanced killing of AML targets. These data suggest that reovirus has the potential as both a direct cytotoxic and an immunotherapeutic agent for the treatment of AML.
Roulstone V, Khan K, Pandha HS, Rudman S, Coffey M, Gill GM, Melcher AA, Vile R, Harrington KJ, de Bono J, Spicer J (2014) Phase I trial of cyclophosphamide as an immune modulator for optimizing oncolytic reovirus delivery to solid tumors., Clin Cancer Res 21 (6) pp. 1305-1312
PURPOSE: Reovirus is a wild-type oncolytic virus that is ubiquitous in the environment; most patients are therefore preimmune. Therapeutic administration leads to an increase in neutralizing antireovirus antibody (NARA) titer. We hypothesized that if NARA limited reovirus antitumor activity, the effect might be attenuated by coadministration of cyclophosphamide. EXPERIMENTAL DESIGN: In a phase I study, patients with advanced cancer received cyclophosphamide 3 days before intravenous reovirus serotype 3 Dearing (RT3D). The primary objective was to reduce the resulting rise in NARA titer. Cyclophosphamide dose was escalated from 25-1,000 mg/m(2) through nine cohorts; we aimed to define a well-tolerated immunomodulatory dose. RESULTS: The combination was well tolerated in 36 patients, with grade 3/4 toxicities only seen at or above the maximum tolerated dose of cyclophosphamide, which was 800 mg/m(2) combined with reovirus. Immunosuppressive effect, defined as maintaining NARA titer rise below a predefined threshold, was observed in only one patient. Furthermore, despite expected myelosuppression seen at higher cyclophosphamide doses, no changes in T-cell subsets, including Tregs, occurred with dose escalation. Viable virus was detected in association with peripheral blood mononuclear cells (PBMC) from 14% of patients 10 days after the last RT3D injection, despite high plasma NARA titer, demonstrating a potential mechanism for prolonged evasion of neutralization by reovirus. CONCLUSIONS: Coadministration of cyclophosphamide with reovirus is safe, but does not attenuate host antiviral responses. Alternative immunomodulation approaches should be explored, but association with PBMCs may allow reovirus to persist and evade even high levels of neutralizing antibodies.
Ismail M, Kevin H, Morgan R, Davies J, Pandha H (2009) ENHANCING PROSTATE CANCER CRYOTHERAPY USING TUMOUR NECROSIS FACTOR RELATED APOPTOSIS-INDUCING LIGAND (TRAIL) SENSITISATION IN A NOVEL IN VITRO MODEL, JOURNAL OF UROLOGY 181 (4) pp. 189-190 ELSEVIER SCIENCE INC
Roulstone V, Twigger K, Zaidi S, Pencavel T, Kyula JN, White C, McLaughlin M, Seth R, Karapanagiotou EM, Mansfield D, Coffey M, Nuovo G, Vile RG, Pandha HS, Melcher AA, Harrington KJ (2012) Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy., Gene Ther
Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin-taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin-paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin-taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.Gene Therapy advance online publication, 16 August 2012; doi:10.1038/gt.2012.68.
Ismail M, Morgan R, Davies J, Pandha H (2009) INHIBITION OF THE AQUAPORIN WATER CHANNELS INCREASES THE SENSITIVITY OF PROSTATE CANCER CELLS TO FREEZING INJURY., JOURNAL OF UROLOGY 181 (4) pp. 185-185 ELSEVIER SCIENCE INC
Kottke T, Chester J, Ilett E, Thompson J, Diaz R, Coffey M, Selby P, Nuovo G, Pulido J, Mukhopadhyay D, Pandha H, Harrington K, Melcher A, Vile R (2011) Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy, Molecular Therapy 19 (10) pp. 1802-1812
We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro-and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses. © 2011 The American Society of Gene & Cell Therapy.
Heinemann L, Simpson GR, Boxall A, Kottke T, Relph KL, Vile R, Melcher A, Prestwich R, Harrington KJ, Morgan R, Pandha HS (2011) Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer., BMC Cancer 11 Biomed Central
Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication.
Yap TA, Brunetto A, Pandha H, Harrington K, de Bono JS (2008) Reovirus therapy in cancer: has the orphan virus found a home?, EXPERT OPINION ON INVESTIGATIONAL DRUGS 17 (12) pp. 1925-1935 INFORMA HEALTHCARE
Pandha HS, Protheroe A, Wylie J, Parker C, Chambers J, Bell S, Munzert G (2008) An open label phase II trial of BI 2536, a novel Plk1 inhibitor, in patients with metastatic hormone refractory prostate cancer (HRPC), JOURNAL OF CLINICAL ONCOLOGY 26 (15) AMER SOC CLINICAL ONCOLOGY
Michael A, Pandha H (2013) Presentation and symptomatology of prostate cancer, pp. 467-471
© 2013 Springer-Verlag London. All rights are reserved.Prostate cancer can present at any stage of the disease and very frequently does not cause any symptoms at all. Most cancers arise in the periphery of the prostate gland and cause symptoms only when they have grown to compress the urethra or invade the sphincter [1]. In recent years, more and more of prostate cancer patients from the western hemisphere are diagnosed at an earlier stage due to rising prevalence of prostate-specific antigen (PSA) testing [2]. A study by Cooperberg et al. analyzed trends in clinical presentation in 2,078 men diagnosed between 1989 and 2001. The proportion of patients with low-risk tumor characteristics rose from 29.8 % in 1989-1992 to 45.3 % in 1999-2001 [3]. Studies based on the Department of Defense Center for Prostate Disease (CPDR) found downward migration at higher stage [3]. The percentage of patients presenting with locally advanced (T3 to T4) disease fell from 19.2 % in 1988 to 4.4 % in 1998; rates of metastatic disease at diagnosis likewise declined from 14.1 % in 1988 to 3.3 % in 1998.
Simpson GR, Ajaz M, Launchbury FA, Bolton G, Melcher AA, Harrington KJ, Au GG, Shafren DR, Pandha HS (2014) Major synergy between Coxsackievirus A21 (CAVATAK (TM)) and radiotherapy or chemotherapy in bladder cancer, HUMAN GENE THERAPY 25 (12) pp. A13-A13 MARY ANN LIEBERT, INC
White CL, Twigger KR, Vidal L, De Bono JS, Coffey M, Heinemann L, Morgan R, Merrick A, Errington F, Vile RG, Melcher AA, Pandha HS, Harrington KJ (2008) Characterization of the adaptive and innate immune response to intravenous oncolytic reovirus (Dearing type 3) during a phase I clinical trial, GENE THERAPY 15 (12) pp. 911-920 NATURE PUBLISHING GROUP
Szulkin R, Whitington T, Eklund M, Aly M, Eeles RA, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Southey MC, Fitzgerald LM, Henderson BE, Schumacher F, Haiman CA, Schleutker J, Wahlfors T, Tammela TLJ, Nordestgaard BG, Key TJ, Travis RC, Neal DE, Donovan JL, Hamdy FC, Pharoah P, Pashayan N, Khaw K-T, Stanford JL, Thibodeau SN, McDonnell SK, Schaid DJ, Maier C, Vogel W, Luedeke M, Herkommer K, Kibel AS, Cybulski C, Lubinski J, Kluzniak W, Cannon-Albright L, Brenner H, Butterbach K, Stegmaier C, Park JY, Sellers T, Lim H-Y, Slavov C, Kaneva R, Mitev V, Batra J, Clements JA, Spurdle A, Teixeira MR, Paulo P, Maia S, Pandha H, Michael A, Kierzek A, Gronberg H, Wiklund F (2015) Prediction of Individual Genetic Risk to Prostate Cancer Using a Polygenic Score, PROSTATE 75 (13) pp. 1467-1474 WILEY-BLACKWELL
Prestwich RJ, Errington F, Harrington KJ, Pandha HS, Selby P, Melcher A (2008) Oncolytic viruses: do they have a role in anti-cancer therapy?, Clin Med Oncol 2 pp. 83-96
Oncolytic viruses are replication competent, tumor selective and lyse cancer cells. Their potential for anti-cancer therapy is based upon the concept that selective intratumoral replication will produce a potent anti-tumor effect and possibly bystander or remote cell killing, whilst minimizing normal tissue toxicity. Viruses may be naturally oncolytic or be engineered for oncolytic activity, and possess a host of different mechanisms to provide tumor selectivity. Clinical use of live replicating viruses is associated with a unique set of safety issues. Clinical experience has so far provided evidence of limited efficacy and a favourable toxicity profile. The interaction with the host immune system is complex. An anti-viral immune response may limit efficacy by rapidly clearing the virus. However, virally-induced cell lysis releases tumor associated antigens in a 'dangerous' context, and limited evidence suggests that this can lead to the generation of a specific anti-tumor immune response. Combination therapy with chemotherapy or radiotherapy represents a promising avenue for ongoing translation of oncolytic viruses into clinical practice. Obstacles to therapy include highly effective non-specific host mechanisms to clear virus following systemic delivery, immune-mediated clearance, and intratumoral barriers limiting virus spread. A number of novel strategies are now under investigation to overcome these barriers. This review provides an overview of the potential role of oncolytic viruses, highlighting recent progress towards developing effective therapy and asks if they are a realistic therapeutic option at this stage.
Gray S, Metcalf S, Boxall A, Middleton G, Bagwan I, Pandha H, Morgan R (2013) The chorio-allantoicmembrane (CAM) model for testing HOX gene antagonism in pancreatic cancer, CANCER RESEARCH 73 (8) AMER ASSOC CANCER RESEARCH
De Paoli M, Perco P, Mühlberger I, Lukas A, Pandha H, Morgan R, Feng GJ, Marquette C (2015) Disease map-based biomarker selection and pre-validation for bladder cancer diagnostic, Biomarkers 20 (5) pp. 328-337
© 2015 Informa UK Ltd. All rights reserved.Context: Urinary biomarkers are promising as simple alternatives to cystoscopy for the diagnosis of de novo and recurrent bladder cancer. Objective: To identify a highly sensitive and specific biomarker candidate set with potential clinical utility in bladder cancer. Materials and methods: Urinary biomarker concentrations were determined by ELISA. The performance of individual markers and marker combinations was assessed using ROC analysis. Results: A five-biomarker panel (IL8, MMP9, VEGFA, PTGS2 and EN2) was defined from the candidate set. Discussion and conclusion: This panel showed a better overall performance than the best individual marker. Further validation studies are needed to evaluate its clinical utility in bladder cancer.
Killick E, Morgan R, Launchbury F, Bancroft E, Page E, Castro E, Kote-Jarai Z, Aprikian A, Blanco I, Clowes V, Domchek S, Douglas F, Eccles D, Evans DG, Harris M, Kirk J, Lam J, Lindeman G, Mitchell G, Pachter N, Selkirk C, Tucker K, Zgajnar J, Eeles R, Pandha H (2013) Role of Engrailed-2 (EN2) as a prostate cancer detection biomarker in genetically high risk men., Sci Rep 3
Controversy surrounds the use of PSA as a biomarker for prostate cancer detection, leaving an unmet need for a novel biomarker in this setting; urinary EN2 may identify individuals with clinically relevant prostate cancer. Male BRCA1 and BRCA2 mutation carriers are at increased risk of clinically significant prostate cancer and may benefit from screening. Urine samples from 413 BRCA1 and BRCA2 mutation carriers and controls were evaluated. Subjects underwent annual PSA screening with diagnostic biopsy triggered by PSA > 3.0?ng/ml; 21 men were diagnosed with prostate cancer. Urinary EN2 levels were measured by ELISA and had a sensitivity of 66.7% and specificity of 89.3% for cancer detection. There was no statistically significant difference in EN2 levels according to genetic status or Gleason score. Urinary EN2 may be useful as a non-invasive early biomarker for prostate cancer detection in genetically high-risk individuals.
Kottke T, Donnelly O, Boisgerault N, Diaz R, Rommelfanger-Konkol D, Pulido J, Thompson J, Mukhopadhyay D, Knutson K, Behrens M, Kaspar R, Coffey M, Selby P, Harrington K, Melcher A, Pandha H, Vile R (2013) Tumor Relapse Is Associated with an Innate Immune Resistant Phenotype across Tumor and Treatment Types Which Can Be Targeted with Rational Second Line Therapies, MOLECULAR THERAPY 21 pp. S249-S249 NATURE PUBLISHING GROUP
Jebar A, Bentham M, Errington-Mais F, Scott K, Peckham-Cooper A, Dave R, Toogood G, Swinson D, Ralph C, Anthoney A, Coffey M, Harrington K, Pandha H, Vile R, Selby P, Melcher A, Griffin S (2014) Combined anti-viral and anti-tumour therapy for virus-associated liver cancer, HUMAN GENE THERAPY 25 (12) pp. A27-A27 MARY ANN LIEBERT, INC
De Paoli M, Gogalic S, Sauer U, Preininger C, Pandha H, Simpson G, Horvath A, Marquette C (2016) Multiplatform Biomarker Discovery for Bladder Cancer Recurrence Diagnosis, DISEASE MARKERS ARTN 4591910 HINDAWI PUBLISHING CORP
Gray S, Pandha HS, Michael A, Middleton G, Morgan R (2011) HOX genes in pancreatic development and cancer., JOP 12 (3) pp. 216-219
The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development and which are subsequently re-expressed in many types of cancer. Some recent studies have shown that HOX genes may have key roles both in pancreatic development and in adult diseases of the pancreas, including cancer. In this review we consider recent advances in elucidating the role of HOX genes in these processes, how they may connect early developmental events to subsequent adult disease, and their potential both as diagnostic markers and therapeutic targets.
Michael A, McGrath S, Annels N, Denyer M, Morgan R, Pandha H (2015) Engrailed 2 protein (EN2) as a novel biomarker in epithelial ovarian cancer, EUROPEAN JOURNAL OF CANCER 51 pp. S91-S91 ELSEVIER SCI LTD
Larkin SET, Johnston HE, Jackson TR, Jamieson DG, Roumeliotis TI, Mockridge CI, Manousopoulou A, Papachristou EK, Brown MD, Clarke NW, Pandha HS, Aukim-Hastie CL, Cragg MS, Garbis SD, Townsend PA (2016) Detection of candidate biomarkers of prostate cancer progression in serum: a depletion-free 3D LC/MS quantitative proteomics pilot study, British Journal of Cancer
Background: Prostate cancer (PCa) is the most common male cancer in the United Kingdom and we aimed to identify clinically relevant biomarkers corresponding to stage progression of the disease.
Methods: We used enhanced proteomic profiling of PCa progression using iTRAQ 3D LC mass spectrometry on high-quality serum samples to identify biomarkers of PCa.
Results: We identified >1000 proteins. Following specific inclusion/exclusion criteria we targeted seven proteins of which two were validated by ELISA and six potentially interacted forming an ?interactome? with only a single protein linking each marker. This network also includes accepted cancer markers, such as TNF, STAT3, NF-ºB and IL6.
Conclusions: Our linked and interrelated biomarker network highlights the potential utility of six of our seven markers as a panel for diagnosing PCa and, critically, in determining the stage of the disease. Our validation analysis of the MS-identified proteins found that SAA alongside KLK3 may improve categorisation of PCa than by KLK3 alone, and that TSR1, although not significant in this model, might also be a clinically relevant biomarker.
Alamara C, Karapanagiotou EM, Tourkantonis I, Xyla V, Maurer CC, Lykourinas M, Pandha H, Syrigos KN (2008) Renal oncocytoma: a case report and short review of the literature., Eur J Intern Med 19 (7) pp. e67-e69
Pandha H, Pawelec G (2015) Immune checkpoint targeting as anti-cancer immunotherapy: promises, questions, challenges and the need for predictive biomarkers at ASCO 2015, CANCER IMMUNOLOGY IMMUNOTHERAPY 64 (9) pp. 1071-1074 SPRINGER
Kyula JN, Khan AA, Mansfield D, Karapanagiotou EM, McLaughlin M, Roulstone V, Zaidi S, Pencavel T, Touchefeu Y, Seth R, Chen NG, Yu YA, Zhang Q, Melcher AA, Vile RG, Pandha HS, Ajaz M, Szalay AA, Harrington KJ (2013) Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in (V600D/E)BRAF mutant melanoma depends on JNK and TNF-± signaling., Oncogene 33 (13) pp. 1700-1712
Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of-concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV-1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in (V600D)BRAF/(V600E)BRAF mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in (V600D)BRAF/(V600E)BRAF mutant cell lines and this was associated with TNF-± secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-± secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors.
Harrington KJ, Melcher A, Vassaux G, Pandha HS, Vile RG (2008) Exploiting synergies between radiation and oncolytic viruses, CURRENT OPINION IN MOLECULAR THERAPEUTICS 10 (4) pp. 362-370 THOMSON SCIENTIFIC
Roberts A, Serrano M, Vantourout P, Dieli F, Pandha H, Hayday AC (2010) Expansion of autologous human V gamma 9V delta 2 T cells ex vivo: potential for adoptive T cell therapy of prostate cancer, IMMUNOLOGY 131 pp. 119-119 WILEY-BLACKWELL PUBLISHING, INC
Boisgerault N, Pulido J, Kottke T, Donnelly O, Celis E, Thompson J, Diaz R, Harrington K, Pandha H, Selby P, Melcher A, Vile R (2013) Tumor Recurrences Share Immunogenic Antigens across Both Tumor Types and Primary Treatments Which Can Be Therapeutically Targeted with VSV-cDNA Libraries, MOLECULAR THERAPY 21 pp. S152-S152 NATURE PUBLISHING GROUP
Davies NM, Gaunt TR, Lewis SJ, Holly J, Donovan JL, Hamdy FC, Kemp JP, Eeles R, Easton D, Kote-Jarai Z, Al Olama AA, Benlloch S, Muir K, Giles GG, Wiklund F, Gronberg H, Haiman CA, Schleutker J, Nordestgaard BG, Travis RC, Neal D, Pashayan N, Khaw K-T, Stanford JL, Blot WJ, Thibodeau S, Maier C, Kibel AS, Cybulski C, Cannon-Albright L, Brenner H, Park J, Kaneva R, Batra J, Teixeira MR, Pandha H, Lathrop M, Smith GD, Martin RM (2015) The effects of height and BMI on prostate cancer incidence and mortality: a Mendelian randomization study in 20,848 cases and 20,214 controls from the PRACTICAL consortium, CANCER CAUSES & CONTROL 26 (11) pp. 1603-1616 SPRINGER
Michael A, Riley, C, Bokaee S, Denyer M, Pandha H, Annels N (2011) EN2: A candidate antigen for the development of targeted therapies in ovarian cancer., JCO (J Clin)
Background: Ovarian cancer remains the most lethal gynaecologic tumour in the Western world. Stimulation of the immune system to consolidate response to chemotherapy can potentially be beneficial however so far none of the vaccination strategies have offered survival advantage. Thus identifying and targeting clinically relevant antigens for immunotherapy continues to be an important research strategy. We have evaluated Engrailed-2 (EN2) as a potential target for vaccine strategy. EN2 is a homeodomain-containing transcription factor with a multifunctional role in neural development. There is evidence that over-expression of EN2 protein maybe linked to tumour development. Methods: Ovarian cancer cell lines were analysed by FACS for EN2 cell surface expression. EN2 expression in ovarian cancer tissue arrays were done by immunohistochemistry. A serum analysis (ELISA) was done to evaluate the presence of antibodies to EN2 in ovarian cancer patients and age-matched controls. A set of potentially immunogenic HLA-A2 restricted epitopes from the EN2 protein was identified using a computer algorithm SYFPEITHI. These peptides have been tested on HLA-A2 positive ovarian cancer patients? PBMC using an in vitro culture method. The specificity of these T cell lines was analysed against T2 target cells loaded with or without EN2 peptides Results: Cell surface expression of EN2 was observed in ovarian cancer cell lines OVCAR3, OV90, CaOV-3, ES-2 and SKOV-3 of which ES-2 and SKOV3 showed strong expression. EN2 was also present in approximately 80% of ovarian cancer tissues whereas EN-2 expression was very low (
Annels NE, Riley C, Bokaee S, Denyer M, Simpson GR, Pandha H (2010) EN2: A Novel Immunotherapeutic Target for Melanoma, JOURNAL OF IMMUNOTHERAPY 33 (8) pp. 891-891 LIPPINCOTT WILLIAMS & WILKINS
Ravaud A, Motzer RJ, Pandha H, Staehler M, George DJ, Pantuck A, Patel A, Gerletti P, Chen L, Patard J (2012) SUNITINIB TREATMENT OF RENAL ADJUVANT CANCER (S-TRAC): A RANDOMIZED, DOUBLE-BLIND, PHASE III STUDY OF SUNITINIB VS. PLACEBO IN SUBJECTS AT HIGH RISK OF RECURRENT RENAL CELL CARCINOMA (RCC), ANNALS OF ONCOLOGY 23 pp. 292-293 OXFORD UNIV PRESS
Lord R, Nair S, Schache A, Spicer J, Somaihah N, Khoo V, Pandha H (2007) Low dose metronomic oral cyclophosphamide for hormone resistant prostate cancer: A phase II study, JOURNAL OF UROLOGY 177 (6) pp. 2136-2140 ELSEVIER SCIENCE INC
Heinemann L, Kottke T, Vile R, Coffey MC, Harrington K, Melcher A, Pandha HS (2008) Synergistic Anti-Tumor Activity of Oncolytic Reovirus and Docetaxel in a PC-3 Prostate Cancer Mouse Model, JOURNAL OF IMMUNOTHERAPY 31 (9) pp. 951-952 LIPPINCOTT WILLIAMS & WILKINS
Horvath A, Simpson GR, Coffin RS, Mostafid AH, Pandha H (2011) Update on a novel intravesical therapy for non muscle invasive bladder cancer: Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic herpes simplex virus, BRITISH JOURNAL OF SURGERY 98 (6) pp. E2-E2 WILEY-BLACKWELL
Coward JIG, Larbi ED, Pandha H, Michael A (2011) The effect of age on first-line sunitinib treatment in patients with renal cell carcinoma (RCC)., J Clin Oncol 29: 2011 (suppl; abstr e15096)
Background: Sunitinib is a first line treatment for majority of patients with metastatic RCC. The recommended dose of 50mg often results in a spectrum of serious side effects which subsequently lead to dose reduction and may have an impact on response rates. Methods: We conducted a retrospective analysis of 62 RCC patients from single institution treated with sunitinib between September 2007-May 2010. Patients were stratified according to age groups, into d 70 year old (y.o.) and > 70 y.o. to compare tolerability, response rates and median survival. Results: All patients were evaluable for toxicity, 55 patients were evaluable for response. 38 (61.2%) were d 70 y.o. and 24 (38.8%) were >70y.o. 2 patients (5%) of d70 and 5 (20%) of > 70y.o. were non-evaluable for response due to early treatment discontinuation. The response rate was 36% in d70y.o. and 21% in >70 y.o., stable disease (SD) was observed in 41% d70 y.o. vs 47% in the older age group and progressive disease PD:22% vs 31.5% respectively. 24 (38.7%) of patients required dose reductions after the first or second cycle- 12 (33%) in d70 vs 11 (59%) in >70 yrs old. A small number of patients presented with PS 2 and these were started on a reduced dose of 37.5mg: 3 (8%) in d70y.o. and 11 (58%) > 70y.o. Toxcities were comparable in both groups however grade 3 palmar-plantar erythema (PPE) and mucositis (18% vs 1.6% and 18 vs 8% respectively) were more prevalent in the younger cohort. Grade 3 diarrhoea and fatigue were more common in older patients (10% in >70y.o vs 1.6% in d70y.o. and 16% vs 9.6% respectively). Median survival was 23 months for both age groups. Conclusions: Elderly patients more commonly require dose reduction due to poor performance status and toxicity profile. The objective response rate is lower with the lower dose intensity however the rate of disease stabilisation is comparable in both groups. The lower dose of Sunitinib is well tolerated in the elderly and this regimen should be considered for older patients with poor performance status.
Hingorani M, White CL, Zaidi S, Pandha HS, Melcher AA, Bhide SA, Nutting CM, Syrigos KN, Vile RG, Vassaux G, Harrington KJ (2010) Therapeutic Effect of Sodium Iodide Symporter Gene Therapy Combined With External Beam Radiotherapy and Targeted Drugs That Inhibit DNA Repair, MOLECULAR THERAPY 18 (9) pp. 1599-1605 NATURE PUBLISHING GROUP
Kottke T, Hall G, Pulido J, Diaz RM, Thompson J, Chong H, Selby P, Coffey M, Pandha H, Chester J, Melcher A, Harrington K, Vile R (2010) Antiangiogenic cancer therapy combined with oncolytic virotherapy leads to regression of established tumors in mice, JOURNAL OF CLINICAL INVESTIGATION 120 (5) pp. 1551-1560 AMER SOC CLINICAL INVESTIGATION INC
Qiao J, Wang H, Kottke T, White C, Twigger K, Diaz RM, Thompson J, Selby P, de Bono J, Melcher A, Pandha H, Coffey M, Vile R, Harrington K (2008) Cyclophosphamide facilitates antitumor efficacy against subcutaneous tumors following intravenous delivery of reovirus, CLINICAL CANCER RESEARCH 14 (1) pp. 259-269 AMER ASSOC CANCER RESEARCH
Roulstone V, Twigger K, Zaidi S, Pencavel T, Kyula JN, White C, McLaughlin M, Seth R, Karapanagiotou EM, Mansfield D, Coffey M, Nuovo G, Vile RG, Pandha HS, Melcher AA, Harrington KJ (2013) Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy, Gene Therapy 20 (5) pp. 521-528
Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin-taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin-paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin-taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.
Annels NE, Denyer M, Pandha H (2010) Increased Myeloid Derived Suppressor Cells in Advanced Prostate Cancer, J IMMUNOTHER 33 (8) pp. 890-891 LIPPINCOTT WILLIAMS & WILKINS
Heinemann L, Simpson GR, Annels NE, Vile R, Melcher A, Prestwich R, Harrington KJ, Pandha HS (2010) The Effect of Cell Cycle Synchronization on Tumor Sensitivity to Reovirus Oncolysis, MOLECULAR THERAPY 18 (12) pp. 2085-2093 NATURE PUBLISHING GROUP
Koropouli E, Manolopoulus L, Pandha H, Syrigos KN (2009) The biological role of mTOR in the pathogenesis of solid tumors: An overview, Current Enzyme Inhibition 5 (1) pp. 51-65
Mackenzie Ross AD, Hossain M, Bennett DC, Cook MG, Chong H, Pandha HS (2013) Senescence evasion in melanoma progression: Uncoupling of DNA-damage signaling from p53 activation and p21 expression, Pigment Cell and Melanoma Research
The best-established function of the melanoma-suppressor p16 is mediation of cell senescence, a permanent arrest following cell proliferation or certain stresses. The importance of p16 in melanoma suggests indolence of the other major senescence pathway through p53. Little or no p53 is expressed in senescent normal human melanocytes, but p16-deficient melanocytes can undergo p53-mediated senescence. As p16 expression occurs in nevi but falls with progression toward melanoma, we here investigated whether p53-dependent senescence occurs at some stage and, if not, what defects were detectable in this pathway, using immunohistochemistry. Phosphorylated checkpoint kinase 2 (CHEK2) can mediate DNA-damage signaling, and under some conditions senescence, by phosphorylating and activating p53. Remarkably, we detected no prevalent p53-mediated senescence in any of six classes of lesions. Two separate defects in p53 signaling appeared common: in nevi, lack of p53 phosphorylation by activated CHEK2, and in melanomas, defective p21 upregulation by p53 even when phosphorylated. © 2012 John Wiley & Sons A/S.
Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13., Cancer Immunol Immunother
We undertook a comprehensive analysis of circulating myeloid-derived suppressor cells (MDSCs) and T regulatory cells (Tregs) in pancreatic, esophageal and gastric cancer patients and investigated whether MDSCs are an independent prognostic factor for survival. We evaluated a series of plasma cytokines and in particular re-evaluated the Th2 cytokine interleukin-13 (IL-13). Peripheral blood was collected from 131 cancer patients (46 pancreatic, 60 esophageal and 25 gastric) and 54 healthy controls. PBMC were harvested with subsequent flow cytometric analysis of MDSC (HLADR(-) Lin1(low/-) CD33(+) CD11b(+)) and Treg (CD4(+) CD25(+) CD127(low/-) FoxP3(+)) percentages. Plasma IL-2, IL-4, IL-5, IL-6, IL-10, IL-12 (p70), IL-13, IL-17, G-CSF, IFN-³, TNF-± and VEGF levels were analyzed by the Bio-Plex cytokine assay. Plasma arginase I levels were analyzed by ELISA. MDSCs and Tregs were statistically significantly elevated in pancreatic, esophageal and gastric cancer compared with controls, and MDSC numbers correlated with Treg levels. Increasing MDSC percentage was associated with increased risk of death, and in a multivariate analysis, MDSC level was an independent prognostic factor for survival. A unit increase in MDSC percentage was associated with a 22% increased risk of death (hazard ratio 1.22, 95% confidence interval 1.06-1.41). Arginase I levels were also statistically significantly elevated in upper gastrointestinal cancer patients compared with controls. There was Th2 skewing for cytokine production in all three diseases, and importantly there were significant elevations of the pivotal Th2 cytokine interleukin-13, an increase that correlated with MDSC levels.
Gabitass RF, Annels NE, Stocken DD, Pandha HA, Middleton GW (2011) Elevated myeloid-derived suppressor cells in pancreatic, esophageal and gastric cancer are an independent prognostic factor and are associated with significant elevation of the Th2 cytokine interleukin-13, Cancer Immunology, Immunotherapy 60 (10) pp. 1419-1430
Al Olama AA, Kote-Jarai Z, Berndt SI, Conti DV, Schumacher F, Han Y, Benlloch S, Hazelett DJ, Wang Z, Saunders E, Leongamornlert D, Lindstrom S, Jugurnauth-Little S, Dadaev T, Tymrakiewicz M, Stram DO, Rand K, Wan P, Stram A, Sheng X, Pooler LC, Park K, Xia L, Tyrer J, Kolonel LN, Le Marchand L, Hoover RN, Machiela MJ, Yeager M, Burdette L, Chung CC, Hutchinson A, Yu K, Goh C, Ahmed M, Govindasami K, Guy M, Tammela TL, Auvinen A, Wahlfors T, Schleutker J, Visakorpi T, Leinonen KA, Xu J, Aly M, Donovan J, Travis RC, Key TJ, Siddiq A, Canzian F, Khaw KT, Takahashi A, Kubo M, Pharoah P, Pashayan N, Weischer M, Nordestgaard BG, Nielsen SF, Klarskov P, Røder MA, Iversen P, Thibodeau SN, McDonnell SK, Schaid DJ, Stanford JL, Kolb S, Holt S, Knudsen B, Coll AH, Gapstur SM, Diver WR, Stevens VL, Maier C, Luedeke M, Herkommer K, Rinckleb AE, Strom SS, Pettaway C, Yeboah ED, Tettey Y, Biritwum RB, Adjei AA, Tay E, Truelove A, Niwa S, Chokkalingam AP, Cannon-Albright L, Cybulski C, WokoBorczyk D, Kluzniak W, Park J, Sellers T, Lin HY, Isaacs WB, Partin AW, Brenner H, Dieffenbach AK, Stegmaier C, Chen C, Giovannucci EL, Ma J, Stampfer M, Penney KL, Mucci L, John EM, Ingles SA, Kittles RA, Murphy AB, Pandha H, Michael A, Kierzek AM, Blot W, Signorello LB, Zheng W, Albanes D, Virtamo J, Weinstein S, Nemesure B, Carpten J, Leske C, Wu SY, Hennis A, Kibel AS, Rybicki BA, Neslund-Dudas C, Hsing AW, Chu L, Goodman PJ, Klein EA, Zheng SL, Batra J, Clements J, Spurdle A, Teixeira MR, Paulo P, Maia S, Slavov C, Kaneva R, Mitev V, Witte JS, Casey G, Gillanders EM, Seminara D, Riboli E, Hamdy FC, Coetzee GA, Li Q, Freedman ML, Hunter DJ, Muir K, Gronberg H, Neal DE, Southey M, Giles GG, Severi G, Breast and Prostate Cancer Cohort Consortium (BPC3), PRACTICAL (Prostate Cancer Association Group to Investigate Cancer-Associated Alterations in the Genome) Consortium, COGS (Collaborative Oncological Gene-environment Study) Consortium, GAME-ON/ELLIPSE Consortium, Cook MB, Nakagawa H, Wiklund F, Kraft P, Chanock SJ, Henderson BE, Easton DF, Eeles RA, Haiman CA (2014) A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer., Nat Genet 46 (10) pp. 1103-1109
Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P
Kelly Z, Pandha H, Morgan R, Michael A (2012) HXR9 AND PARP INHIBITION -A NOVEL THERAPEUTIC IN OVARIAN CANCER, ANNALS OF ONCOLOGY 23 pp. 325-325 OXFORD UNIV PRESS
Binda E, Perez SM, Pandha H, Eberl M, Hayday A (2010) Monitoring the immunological effects of bisphosphonates in different treatment scenarios, IMMUNOLOGY 131 pp. 117-117 WILEY-BLACKWELL PUBLISHING, INC
Steele L, Errington F, Prestwich R, Ilett E, Harrington K, Pandha H, Coffey M, Selby P, Vile R, Melcher A (2011) Pro-inflammatory cytokine/chemokine production by reovirus treated melanoma cells is PKR/NF-kappa B mediated and supports innate and adaptive anti-tumour immune priming, MOLECULAR CANCER 10 ARTN 20 BIOMED CENTRAL LTD
Tuan J, Pandha H, Corbishley C, Khoo V (2012) Basaloid carcinoma of the prostate: A literature review with case report, Indian Journal of Urology 28 (3) pp. 322-324
Basal cell carcinoma of the prostate (BCP) is a neoplasm composed of prostatic basal cells. There are only a few publications outlining the diagnosis, treatment, prognosis and outcome for BCP. Traditionally surgery has been used but these tumors also respond to concomitant chemo-radiotherapy. Using a BCP case report treated with radical chemo-radiotherapy from a chemotherapy regimen used in anal cancers, we propose an alternative management to the traditional options of radical surgery and radical radiotherapy.
Donnelly OG, Errington-Mais F, Prestwich R, Harrington K, Pandha H, Vile R, Melcher AA (2011) Recent Clinical Experience With Oncolytic Viruses., Curr Pharm Biotechnol
There has been interest in using viruses to treat cancer for over a century. Recent clinical efforts, driven on by significant preclinical advances, have focussed on the safety of using replication-competent viruses. Recently published clinical trials of six oncolytic viruses (adenovirus, reovirus, measles, herpes simplex, Newcastle disease virus and vaccinia) have added to the accumulating data that endorse oncolytic viruses as a safe and well tolerated treatment approach. Conclusive evidence of efficacy remains to be demonstrated, but randomised clinical trials are now underway.
Ismail M, Morgan R, Davies J, Pandha H (2008) Immunoregulatory effects of cryo-treated prostate cancer cells on human dendritic cells using a novel in vitro cryotherapy model, JOURNAL OF UROLOGY 179 (4) pp. 48-48 ELSEVIER SCIENCE INC
Kottke T, Donnelly O, Boisgerault N, Diaz R, Thompson J, Chester J, Pandha H, Harrington K, Melcher A, Vile R (2012) Characterization of the Mechanisms of Tumor Dormancy and Recurrence Following Front Line Immuno-, Viro- or Suicide Gene-, Therapy, MOLECULAR THERAPY 20 pp. S268-S268 NATURE PUBLISHING GROUP
Adair RA, Roulstone V, Scott KJ, Morgan R, Nuovo GJ, Fuller M, Beirne D, West EJ, Jennings VA, Rose A, Kyula J, Fraser S, Dave R, Anthoney DA, Merrick A, Prestwich R, Aldouri A, Donnelly O, Pandha H, Coffey M, Selby P, Vile R, Toogood G, Harrington K, Melcher AA (2012) Cell carriage, delivery, and selective replication of an oncolytic virus in tumor in patients., Sci Transl Med 4 (138)
Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. However, how they evade the antiviral immune response and their selective delivery to, and replication in, tumor over normal tissue has not been investigated in humans. Here, we treated patients with a single cycle of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Tracking the viral genome in the circulation showed that reovirus could be detected in plasma and blood mononuclear, granulocyte, and platelet cell compartments after infusion. Despite the presence of neutralizing antibodies before viral infusion in all patients, replication-competent reovirus that retained cytotoxicity was recovered from blood cells but not plasma, suggesting that transport by cells could protect virus for potential delivery to tumors. Analysis of surgical specimens demonstrated greater, preferential expression of reovirus protein in malignant cells compared to either tumor stroma or surrounding normal liver tissue. There was evidence of viral factories within tumor, and recovery of replicating virus from tumor (but not normal liver) was achieved in all four patients from whom fresh tissue was available. Hence, reovirus could be protected from neutralizing antibodies after systemic administration by immune cell carriage, which delivered reovirus to tumor. These findings suggest new preclinical and clinical scheduling and treatment combination strategies to enhance in vivo immune evasion and effective intravenous delivery of oncolytic viruses to patients in vivo.
Ravaud A, Motzer RJ, Pandha Hardev S., George DJ, Pantuck AJ, Patel A, Chang YH, Escudier B, Donskov F, Magheli A, Carteni G, Laguerre B, Tomczak P, Breza J, Gerletti P, Lechuga M, Lin X, Martini JF, Ramaswamy K, Casey M, Staehler M, Patard JJ (2016) Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy, New England Journal of Medicine 375 pp. 2246-2254 Massachusetts Medical Society
BACKGROUND
Sunitinib, a vascular endothelial growth factor pathway inhibitor, is an effective treatment for metastatic renal-cell carcinoma. We sought to determine the efficacy and safety of sunitinib in patients with locoregional renal-cell carcinoma at high risk for tumor recurrence after nephrectomy.
METHODS
In this randomized, double-blind, phase 3 trial, we assigned 615 patients with locoregional, high-risk clear-cell renal-cell carcinoma to receive either sunitinib (50 mg per day) or placebo on a 4-weeks-on, 2-weeks-off schedule for 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. The primary end point was disease-free survival, according to blinded independent central review. Secondary end points included investigator-assessed disease-free survival, overall survival, and safety.
RESULTS
The median duration of disease-free survival was 6.8 years (95% confidence interval [CI], 5.8 to not reached) in the sunitinib group and 5.6 years (95% CI, 3.8 to 6.6) in the placebo group (hazard ratio, 0.76; 95% CI, 0.59 to 0.98; P=0.03). Overall survival data were not mature at the time of data cutoff. Dose reductions because of adverse events were more frequent in the sunitinib group than in the placebo group (34.3% vs. 2%), as were dose interruptions (46.4% vs. 13.2%) and discontinuations (28.1% vs. 5.6%). Grade 3 or 4 adverse events were more frequent in the sunitinib group (48.4% for grade 3 events and 12.1% for grade 4 events) than in the placebo group (15.8% and 3.6%, respectively). There was a similar incidence of serious adverse events in the two groups (21.9% for sunitinib vs. 17.1% for placebo); no deaths were attributed to toxic effects.
CONCLUSIONS
Among patients with locoregional clear-cell renal-cell carcinoma at high risk for tumor recurrence after nephrectomy, the median duration of disease-free survival was significantly longer in the sunitinib group than in the placebo group, at a cost of a higher rate of toxic events. (Funded by Pfizer; S-TRAC ClinicalTrials.gov number, NCT00375674.)
McGrath SE, Michael A, Pandha H, Morgan R (2013) Engrailed homeobox transcription factors as potential markers and targets in cancer., FEBS Lett 587 (6) pp. 549-554
Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles.
McGrath S, Annels NE, Madhuri TK, Haagsma B, Larbi ED, Pandha HS, Michael A (2012) Engrailed protein: A cancer-specific marker in epithelial ovarian cancer, JOURNAL OF CLINICAL ONCOLOGY 30 (15) AMER SOC CLINICAL ONCOLOGY
Michael A, Politi E, Havranek E, Corbishley C, Karapanagiotou L, Anderson C, Relph K, Syrigos KN, Pandha H (2007) Prognostic significance of erythropoietin expression in human renal cell carcinoma, BJU INTERNATIONAL 100 (2) pp. 291-294 BLACKWELL PUBLISHING
Errico MC, Felicetti F, Bottero L, Mattia G, Felli N, Petrini M, Bellenghi M, Pandha HS, Morgan R, Care A (2014) THE ABROGATION OF THE HOXB7/PBX2 COMPLEX INDUCES APOPTOSIS IN MELANOMA THROUGH THE MIR-221&222-c-FOS PATHWAY, ANTICANCER RESEARCH 34 (10) pp. 5895-5896 INT INST ANTICANCER RESEARCH
Spicer J, Plunkett T, Somaiah N, Chan S, Kendall A, Bolunwu N, Pandha H (2005) Phase II study of oral capecitabine in patients with hormone-refractory prostate cancer, PROSTATE CANCER AND PROSTATIC DISEASES 8 (4) pp. 364-368 NATURE PUBLISHING GROUP
Meyer B, Denyer M, Morgan R, Pandha H (2007) Cellular effects of phosphoramide mustard, the active metabolite of cyclophosphamide, on naturally-occuring human CD4(+) CD25(+) regulatory T cells, JOURNAL OF IMMUNOTHERAPY 30 (8) pp. 887-887 LIPPINCOTT WILLIAMS & WILKINS
Adair RA, Scott KJ, Fraser S, Errington-Mais F, Pandha H, Coffey M, Selby P, Cook GP, Vile R, Harrington KJ, Toogood G, Melcher AA (2012) Cytotoxic and immune-mediated killing of human colorectal cancer by reovirus-loaded blood and liver mononuclear cells., Int J Cancer
Reovirus is a promising oncolytic virus, acting by both direct and immune-mediated mechanisms, although its potential may be limited by inactivation after systemic delivery. Our study addressed whether systemically delivered reovirus might be shielded from neutralising antibodies by cell carriage and whether virus-loaded blood or hepatic innate immune effector cells become activated to kill colorectal cancer cells metastatic to the liver in human systems. We found that reovirus was directly cytotoxic against tumour cells but not against fresh hepatocytes. Although direct tumour cell killing by neat virus was significantly reduced in the presence of neutralising serum, reovirus was protected when loaded onto peripheral blood mononuclear cells, which may carry virus after intravenous administration in patients. As well as handing off virus for direct oncolytic killing, natural killer (NK) cells within reovirus-treated blood mononuclear cells were stimulated to kill tumour targets, but not normal hepatocytes, in a Type I interferon-dependent manner. Similarly, NK cells within liver mononuclear cells became selectively cytotoxic towards tumour cells when activated by reovirus. Hence, intravenous reovirus may evade neutralisation by serum via binding to circulating mononuclear cells, and this blood cell carriage has the potential to investigate both direct and innate immune-mediated therapy against human colorectal or other cancers metastatic to the liver.
Kottke T, Chester J, Ilett E, Thompson J, Diaz R, Coffey M, Selby P, Nuovo G, Pulido J, Mukhopadhyay D (2011) Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy., Mol Ther 19 (10) pp. 1802-1812
We have previously reported that a burst of vascular endothelial growth factor (VEGF) signaling to tumor-associated endothelium induces a proviral state, during which systemically delivered oncolytic reovirus can replicate in endothelium, thereby inducing immune-mediated vascular collapse and significant antitumor therapy. Using chimeric receptors, we show here that induction of the proviral state proceeds through VEGFR2, but not VEGFR1, signaling in endothelial cells. In contrast, innate immune activation by reovirus-exposed endothelial cells was predominantly through VEGFR1. By screening conventional chemotherapies for their ability to induce similar effects in combination with reovirus both in vitro and in vivo, we observed that the proviral state could also be induced in endothelial cells exposed to VEGF during rebound from paclitaxel-mediated inhibition of VEGF signaling. We translated these in vitro findings in vivo by careful scheduling of paclitaxel chemotherapy with systemic virotherapy, neither of which alone had therapeutic effects against B16 tumors. Systemic availability of reovirus during endothelial cell recovery from paclitaxel treatment allowed for endothelial replication of the virus, immune-mediated therapy, and tumor cures. Therefore, careful scheduling of combination viro- and chemotherapies, which preclinical testing suggests are individually ineffective against tumor cells, can lead to rational new clinical protocols for systemic treatments with oncolytic viruses.
White CL, Menghistu T, Twigger KR, Searle PF, Bhide SA, Vile RG, Melcher AA, Pandha HS, Harrington KJ (2008) Escherichia coli nitroreductase plus CB1954 enhances the effect of radiotherapy in vitro and in vivo, GENE THERAPY 15 (6) pp. 424-433 NATURE PUBLISHING GROUP
Hingorani M, Spitzweg C, Vassaux G, Newbold K, Melcher A, Pandha H, Vile R, Harrington K (2010) The Biology of the Sodium Iodide Symporter and its Potential for Targeted Gene Delivery, CURR CANCER DRUG TAR 10 (2) pp. 242-267 BENTHAM SCIENCE PUBL LTD
McGrath SE, Michael A, Pandha H, Morgan R (2013) Engrailed homeobox transcription factors as potential markers and targets in cancer, FEBS Letters 587 (6) pp. 549-554
Engrailed (En) is a member of the homeobox gene family, which encodes a homeodomain-containing transcription factor that is essential during early development. The only known site of normal adult Engrailed protein (EN) expression is in the nervous system, and it has been implicated in the development of both young-onset Parkinson's disease as well as autism. Over-expression of EN has been linked to tumour development in adults, particularly in breast, prostate, melanoma and ovarian cancers, and there is a growing interest in its role as a diagnostic and prognostic biomarker. It is hoped that further work may confirm associations between En expression and therapy-resistant, poor prognosis cancers, similar to that identified with other homeobox gene profiles. © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
Morgan RGL, Bryan R, Javed S, Launchbury F, Zeegers M, Cheng K, James N, Wallace D, Hurst C, Ward D, Knowles M, Pandha HS (2013) Expression of Engrailed-2 (EN2) protein in bladder cancer and its potential utility as a urinary diagnostic biomarker., Eur J Cancer Elsevier
Despite significant advances in our understanding of the molecular pathology of bladder cancer, it remains a significant health problem with high morbidity and mortality associated with muscle-invasive bladder cancer (stages T2+), and high costs associated with the surveillance of non-muscle-invasive bladder cancer (NMIBC, stages Ta/T1/Tis). Moreover, current diagnostic biomarkers are suboptimal and of poor utility for low grade disease and surveillance. In this study, we show that the Engrailed-2 (EN2) transcription factor is expressed in, and secreted by, bladder cancer cell lines and patient tumour specimens, justifying an evaluation of urinary EN2 as a diagnostic biomarker in bladder cancer using archived samples from an established biospecimen collection. In patients with NMIBC, urinary EN2 was detected in most cases with an overall sensitivity of 82% and specificity of 75%. The sensitivity for stage Ta and T1 tumours was 71% and 76%, respectively, and 94% for stage T2+ tumours. This compares favourably with existing markers. The sensitivity for tumour grades 1, 2 and 3 was 69%, 78% and 87%, respectively. Thus urinary EN2 has the potential to be a more sensitive and specific protein biomarker for NMIBC than currently available tests.
Kelly Z, Moller-Levet CS, McGrath S, Butler-Manuel S, Madhuri TK, Kierzek AM, Pandha HS, Morgan RGL, Michael A (2016) The prognostic significance of specific HOX gene expression patterns in ovarian cancer, International Journal of Cancer 139 (7) pp. 1608-1617 Wiley
OBJECTIVE: HOX genes are vital for all aspects of mammalian growth and differentiation, and their dysregulated expression is related to ovarian carcinogenesis. The aim of the current study was to establish the prognostic value of HOX dysregulation as well as its role in platinum resistance. The potential to target HOX proteins through the HOX/PBX interaction was also explored in the context of platinum resistance. METHODS: HOX gene expression was determined in ovarian cancer cell lines and primary EOCs, and compared to expression in normal ovarian epithelium and fallopian tube tissue samples. Statistical analysis included one way ANOVA and t-tests, using statistical software R and GraphPad. RESULTS: 30 of the 39 HOX genes were overexpressed in high grade serous EOC compared to normal tissue, most significant being HOXA3, A9, B13 and C10. We detected a molecular HOX gene-signature that predicted poor outcome: overexpression of HOXB4 and HOXB9 was identified in high grade serous cell lines after platinum resistance developed. Targeting the HOX/PBX dimer with the the HXR9 peptide enhanced the cytotoxicity of cisplatin in platinum-resistant ovarian cancer.CONCLUSIONS: HOX genes are highly dysregulated in ovarian cancer. High expression of HOXA13, B6, C13, D1 and D13 is predictive of poor clinical outcome. Targeting the HOX/PBX dimer in platinum?resistant cancer represents a new therapeutic option that should be further developed and tested in clinical trials.
Lophatananon A, Stewart-Brown S, Kote-Jarai Z, Olama A, Garcia S, Neal D, Hamdy F, Donovan J, Giles G, Fitzgerald L, Southey M, Pharoah P, Pashayan N, Gronberg H, Wiklund F, Aly M, Stanford J, Brenner H, Dieffenbach A, Arndt V, Park J, Lin H, Sellers T, Slavov C, Kaneva R, Mitev V, Batra J, Spurdle A, Clements J, Schleutker J, Nordestgaard B, Wiklund F, Travis R, Haiman C, Thibodeau S, Maier C, Walther V, Blot W, Kibel A, Cybulski C, Cannon-Albright L, Pandha H, Teixeira M, Cook M, Govindasami K, Guy M, Leongamornlert D, Sawyer E, Wilkinson R, Morgan A, Fisher C, Saunders E, Tymrakiewicz M, Livni N, Hazel S, Dadaev T, Cox A, George A, Lane A, Marsden G, Davis M, Brown P, Pedersen J, Hopper J, Karlsson A, Cavalli-Bjoerkman C, Adolfson J, Johansson J, Broms M, Stattin P, Kolb S, Stegmaier C, Zachariah B, Park H, Haley J, Pow-Sang J, Rincon M, Radlein S, Vlahova A, Mitkova A, Kachakova D, Popov E, Christova S, Dikov T, Eckert A, Collins A, Wood G, Malone G, Alexander K, Kerr K, Kedda M, Turner M, Saunders P, Heathcote P, Srinivasan S, Omara T, Yeadon T, Lose F, Easton D, Eeles R, Muir K (2017) Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium, British Journal of Cancer 117 (5) pp. 734-743 Cancer Research UK / Nature Publishing Group
Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a
possible role for its association with the risk of aggressive prostate cancer.
Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a
subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects
and their possible interactions.
Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height 4180cm are at a 22%
increased risk as compared to men with height o173cm (OR 1.22, 95% CI 1.01?1.48). Genetic variants in the growth pathway gene
showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased
risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as
compared to lowest score group.
Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs. Our
findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is
seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.
Kelly Z, Michael A, Butler-Manuel S, Pandha HS, Morgan RGL (2011) HOX genes in ovarian cancer, Journal of Ovarian Research 4 (1) Springer
The HOX genes are a family of homeodomain-containing transcription factors that determine cellular identity during development. Here we review a number of recent studies showing that HOX genes are strongly expressed in ovarian cancer, and that in some cases the expression of specific HOX genes is sufficient to confer a particular identity and phenotype upon cancer cells. We also review the recent advances in elucidating the different functions of HOX genes in ovarian cancer. A literature search was performed using the search terms HOX genes (including specific HOX genes), ovarian cancer and oncogenesis. Articles were accessed through searches performed in ISI Web of Knowledge, PubMed and ScienceDirect. Taken together, these studies have shown that HOX genes play a role in the oncogenesis of ovarian cancer and function in the inhibition of apoptosis, DNA repair and enhanced cell motility. The function of HOX genes in ovarian cancer oncogenesis supports their potential role as prognostic and diagnostic markers, and as therapeutic targets in this disease.
Gogalic S, Sauer U, Doppler S, Heinzel A, Perco P, Lukas A, Simpson G, Pandha H, Horvath A, Preininger C (2017) Validation of a protein panel for the non-invasive detection of recurrent non-muscle invasive bladder cancer, Biomarkers 22 (7) pp. 674-681 Taylor & Francis
Context: About 50?70% of patients with non-muscle invasive bladder cancer (NMIBC) experience relapse of disease. Objective: To establish a panel of protein biomarkers incorporated in a multiplexed microarray (BCa chip) and a classifier for diagnosing recurrent NMIBC. Materials and methods: Urine samples from 45 patients were tested. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis. Results: A multi biomarker panel (ECadh, IL8, MMP9, EN2, VEGF, past recurrences, BCG therapies and stage at diagnosis) was identified yielding an area under the curve of 0.96. Discussion and conclusion: This biomarker panel represents a potential diagnostic tool for noninvasive diagnosis of recurrent NMIBC.
Walker S, Knight L, McCavigan A, Logan G, Berge V, Sherif A, Pandha HS, Warren A, Davidson C, Uprichard A, Blayney J, Price B, Jellema G, Svindland A, McDade S, Eden C, Foster C, Mills I, Neal D, Mason M, Kay E, Waugh D, Harkin D, Watson R, Clarke N, Kennedy R (2017) Molecular Subgroup of Primary Prostate Cancer Presenting with Metastatic Biology, European Urology 72 (4) pp. 509-518 Elsevier
BACKGROUND: Approximately 4-25% of patients with early prostate cancer develop disease recurrence following radical prostatectomy. OBJECTIVE: To identify a molecular subgroup of prostate cancers with metastatic potential at presentation resulting in a high risk of recurrence following radical prostatectomy. DESIGN, SETTING & PARTICIPANTS: Unsupervised hierarchical clustering was performed using gene expression data from 70 primary resections, 31 metastatic lymph nodes and 25 normal prostate samples. Independent assay validation was performed using 322 radical prostatectomy samples from four sites with a mean follow-up of 50.3 months. OUTCOME MEASURES & STATISTICAL ANALYSIS: Molecular subgroups were identified using unsupervised hierarchical clustering. A partial least squares approach was used to generate a gene expression assay. Relationships with outcome (time to biochemical and metastatic recurrence) were analyzed using multivariable Cox regression and log-rank analysis. RESULTS & LIMITATIONS: A molecular subgroup of primary prostate cancer with biology similar to metastatic disease was identified. A 70-transcript signature (Metastatic Assay) was developed and independently validated in the radical prostatectomy samples. Metastatic Assay positive patients had increased risk of biochemical recurrence (Multivariable HR 1.62 [1.13-2.33]; p= 0.0092) and metastatic recurrence (Multivariable HR=3.20 (1.76-5.80); p=0.0001). A combined model with CAPRA-S identified patients at increased risk of biochemical and metastatic recurrence superior to either model alone (HR=2.67 [1.90-3.75]; p
Michael A, Relph KL, Annels NE, Pandha HS (2014) Prostate cancer vaccines., Expert Review of Vaccines 12 (3) pp. 253-262 Taylor & Francis
In 2010, the US FDA approved the first therapeutic cancer vaccine for the treatment of castration refractory prostate cancer - sipuleucel-T. Prostate cancer is an ideal model for cancer vaccine development based on the ready demonstration of humoral and cellular immunity to a range of cancer antigens as well as often slow progression which means that patients who are otherwise well may have a radiologically evaluable minor progression, after conventional treatment and can undergo vaccine therapy over sufficient periods of time, so as to allow the generation of a robust antitumor response. The association of prostate cancer with one of the few serum cancer biomarkers in general use has also allowed assessment of response and risk stratification of patients. In this review, we will examine key aspects of the evolution of prostate cancer vaccines, which provides an accurate prototype for other cancers, and the challenges we face.
Pandha HS, Heinemann L, Simpson GR, Melcher A, Prestwich R, Errington F, Coffey M, Harrington K, Morgan RGL (2009) Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma, Clinical Cancer Research 15 (19) pp. 6158-6166 American Association for Cancer Research
Morgan Richard, Boxall A, Simpson Guy, Michael Agnieszka, Pandha Hardev, Harrington KJ, Gillett C (2012) Targeting the HOX/PBX dimer in breast cancer, Breast Cancer Research and Treatment 136 (2) pp. 389-398 Springer Verlag
The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.
Morgan RGL, Plowright L, Harrington K, Michael A, Pandha HS (2010) Targeting HOX and PBX transcription factors in ovarian cancer, BMC CANCER 10 ARTN 8 BIOMED CENTRAL LTD
Motzer Robert J, Ravaud Alain, Patard Jean-Jacques, Pandha Hardev, George Daniel J, Patel Anup, Chang Yen-Hwa, Escudier Bernard, Donskov Frede, Magheli Ahmed, Carteni Giacomo, Laguerre Brigitte, Tomczak Piotr, Breza Jan, Gerletti Paola, Lechuga Mariajose, Lin Xun, Casey Michelle, Serfass Lucile, Pantuck Allan J, Staehler Michael (2017) Adjuvant Sunitinib for High-risk Renal Cell Carcinoma After Nephrectomy: Subgroup Analyses and Updated Overall Survival Results, European Urology 73 (1) pp. 62-68 Elsevier
Background:
Adjuvant sunitinib significantly improved disease-free survival (DFS)
versus placebo in patients with locoregional renal cell carcinoma (RCC) at high risk
of recurrence after nephrectomy (hazard ratio [HR] 0.76, 95% confidence interval [CI]
0.59?0.98; p = 0.03).
Objective:
To report the relationship between baseline factors and DFS, pattern of
recurrence, and updated overall survival (OS).
Design, setting, and participants: Data for 615 patients randomized to sunitinib
(n = 309) or placebo (n = 306) in the S-TRAC trial.
Outcome measurements and statistical analysis: Subgroup DFS analyses by baseline risk
factors were conducted using a Cox proportional hazards model. Baseline risk factors
included: modified University of California Los Angeles integrated staging system
criteria, age, gender, Eastern Cooperative Oncology Group performance status (ECOG
PS), weight, neutrophil-to-lymphocyte ratio (NLR), and Fuhrman grade.
Results and limitations:
Of 615 patients, 97 and 122 in the sunitinib and placebo arms
developed metastatic disease, with the most common sites of distant recurrence being
lung (40 and 49), lymph node (21 and 26), and liver (11 and 14), respectively. A benefit of
adjuvant sunitinib over placebo was observed across subgroups, including: higher risk
(T3, no or undetermined nodal involvement, Fuhrman grade 2, ECOG PS 1, T4 and/or nodal involvement; hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.55?0.99; p = 0.04),
NLR 3 (HR 0.72, 95% CI 0.54?0.95; p = 0.02), and Fuhrman grade 3/4 (HR 0.73, 95% CI 0.55?
0.98; p = 0.04). All subgroup analyses were exploratory, and no adjustments for multiplicity
were made. Median OS was not reached in either arm (HR 0.92, 95% CI 0.66?1.28; p = 0.6);
67 and 74 patients died in the sunitinib and placebo arms, respectively.
Conclusions:
A benefit of adjuvant sunitinib over placebo was observed across subgroups.
The results are consistent with the primary analysis, which showed a benefit for adjuvant
sunitinib in patients at high risk of recurrent RCC after nephrectomy.
Patient summary:
Most subgroups of patients at high risk of recurrent renal cell carcinoma
after nephrectomy experienced a clinical benefit with adjuvant sunitinib.
Trial registration:
ClinicalTrials.gov NCT00375674.
Kottke Tim, Evgin Laura, Shim Kevin G., Rommelfanger Diana, Boisgerault Nicolas, Zaidi Shane, Diaz Rosa Maria, Thompson Jill, Ilett Elizabeth, Coffey Matt, Selby Peter, Pandha Hardev, Harrington Kevin, Melcher Alan, Vile Richard (2017) Subversion of NK-cell and TNF± Immune Surveillance Drives Tumor Recurrence, Cancer Immunology Research 5 (11) pp. 1029-1045 American Association for Cancer Research
Understanding how incompletely cleared primary tumors transition from minimal residual disease (MRD) into treatment resistant, immune-invisible recurrences has major clinical significance. We show here that this transition is mediated through the subversion of two key elements of innate immune surveillance. In the first, the role of TNFalpha changes from an antitumor effector against primary tumors into a growth promoter for MRD. Second, whereas primary tumors induced a natural killer (NK)-mediated cytokine response characterized by low IL6 and elevated IFNgamma, PD-L1hi MRD cells promoted the secretion of IL6 but minimal IFNgamma, inhibiting both NK cell and T-cell surveillance. Tumor recurrence was promoted by trauma- or infection-like stimuli inducing VEGF and TNFalpha which stimulated the growth of MRD tumors. Finally, therapies which blocked PD1, TNFalpha or NK cells delayed or prevented recurrence. These data show how innate immune surveillance mechanisms, which control infection and growth of primary tumors, are exploited by recurrent, competent tumors and identifies therapeutic targets in patients with MRD known to be at high risk of relapse.
Samson A, Scott K, Taggart D, West E, Wilson E, Nuovo G, Thomson S, Corns R, Mathew R, Fuller M, Kottke T, Thompson J, Ilett E, Cockle J, van Hille P, Sivakumar G, Polson E, Turnbull S, Appleton E, Migneco G, Rose A, Coffey M, Beirne D, Collinson F, Ralph C, Anthoney D, Twelves C, Furness A, Quezada S, Wurdak H, Errington-Mais F, Pandha H, Harrington K, Selby P, Vile R, Griffin S, Stead L, Short S, Melcher A (2018) Intravenous Delivery of Oncolytic Reovirus to Brain Tumor Patients Immunologically Primes for Subsequent Checkpoint Blockade, Science Translational Medicine 10 (422) eaam7577 American Association for the Advancement of Science
Immune checkpoint inhibitors, including those targeting programmed cell death protein 1 (PD-1), are reshaping cancer therapeutic strategies. Evidence suggests, however, that tumor response and patient survival are determined by tumor programmed death-ligand 1 (PD-L1) expression. We hypothesized that preconditioning of the tumor immune microenvironment using targeted, virus-mediated interferon (IFN) stimulation, would upregulate tumor PD-L1 protein expression and increase cytotoxic T cell infiltration, improving the efficacy of subsequent checkpoint blockade. Oncolytic viruses (OVs) represent a promising form of cancer immunotherapy. For brain tumors, almost all studies to date have used direct intralesional injection of OV, because of the largely untested belief that intravenous (i.v.) administration will not deliver virus to this site. Here we show, in a window-of-opportunity clinical study, that i.v. infusion of oncolytic human Orthoreovirus (referred to herein as reovirus), leads to infection of tumor cells subsequently resected as part of standard clinical care, both in high-grade glioma (HGG) and in brain metastases, and increases cytotoxic T cell tumor infiltration relative to patients not treated with virus. We further show that reovirus upregulates IFN-regulated gene expression, as well as the PD-1/PD-L1 axis in tumors, via an IFN-mediated mechanism. Finally, we show that addition of PD-1 blockade to reovirus enhances systemic therapy in a preclinical glioma model. These results support the development of combined systemic immunovirotherapy strategies for the treatment of both primary and secondary tumors in the brain.
Seibert Tyler M, Fan Chun Chieh, Wang Yunpeng, Zuber Verena, Karunamuni Roshan, Parsons J Kellogg, Eeles Rosalind A, Easton Douglas F, Kote-Jarai ZSofia, Al Olama Ali Amin, Garcia Sara Benlloch, Muir Kenneth, Grönberg Henrik, Wiklund Fredrik, Aly Markus, Schleutker Johanna, Sipeky Csilla, Tammela Teuvo LJ, Nordestgaard Børge G, Nielsen Sune F, Weischer Maren, Bisbjerg Rasmus, Røder M Andreas, Iversen Peter, Key Tim J, Travis Ruth C, Neal David E, Donovan Jenny L, Hamdy Freddie C, Pharoah Paul, Pashayan Nora, Khaw Kay-Tee, Maier Christiane, Vogel Walther, Luedeke Manuel, Herkommer Kathleen, Kibel Adam S, Cybulski Cezary, Wokolorczyk Dominika, Kluzniak Wojciech, Cannon-Albright Lisa, Brenner Hermann, Cuk Katarina, Saum Kai-Uwe, Park Jong Y, Sellers Thomas A, Slavov Chavdar, Kaneva Radka, Mitev Vanio, Batra Jyotsna, Clements Judith A, Spurdle Amanda, Teixeira Manuel R, Paulo Paula, Maia Sofia, Pandha Hardev, Michael Agnieszka, Kierzek Andrzej, Karow David S, Mills Ian G, Andreassen Ole A, Dale Anders M (2018) Polygenic hazard score to guide screening for aggressive prostate cancer: development and validation in large scale cohorts, BMJ 360 j5757 pp. 1-7 BMJ Publishing Group
Objectives: Prostate-specific-antigen (PSA) screening resulted in reduced prostate cancer (PCa) mortality in a large clinical trial, but due to many false positives and overdiagnosis of indolent disease, many guidelines do not endorse universal screening and instead recommend an individualized decision based on each patient?s risk. We sought to develop and validate a genetic tool to predict age of aggressive PCa onset and to guide decisions of whom to screen and at what age.
Design: Genotype, PCa status, and age were analyzed to select single-nucleotide polymorphisms (SNPs) associated with PCa diagnosis. These SNPs were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (i.e., not eligible for surveillance per NCCN Guidelines; any of: Gleason score e7, stage T3-T4, PSA e10, nodal metastasis, distant metastasis). The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and screening PSA data. PHS was calculated for these men to test prediction of PCa-free survival.
Setting: Multiple, international PRACTICAL consortium member institutions.
Participants: All PRACTICAL consortium participants of European ancestry with known age, PCa status, and quality-assured iCOGS array genotype data. Development dataset comprised 31,747 men. Validation dataset comprised 6,411 men.
Main outcome measures: PHS prediction of age of onset of aggressive PCa in validation set.
Results: In the independent validation set, PHS calculated from 54 SNPs was a highly significant predictor of age at diagnosis of aggressive PCa (z=11.2, p98th percentile) were compared to those with average PHS (30th-70th percentile), the hazard ratio for aggressive PCa was 2.9.
Conclusions:Polygenic hazard scores give personalized genetic risk estimates that predict for age of onset of aggressive PCa.
Design: Genotype, PCa status, and age were analyzed to select single-nucleotide polymorphisms (SNPs) associated with PCa diagnosis. These SNPs were incorporated into a survival analysis to estimate their effects on age at diagnosis of aggressive PCa (i.e., not eligible for surveillance per NCCN Guidelines; any of: Gleason score e7, stage T3-T4, PSA e10, nodal metastasis, distant metastasis). The resulting polygenic hazard score (PHS) is an assessment of individual genetic risk. The final model was applied to an independent dataset containing genotype and screening PSA data. PHS was calculated for these men to test prediction of PCa-free survival.
Setting: Multiple, international PRACTICAL consortium member institutions.
Participants: All PRACTICAL consortium participants of European ancestry with known age, PCa status, and quality-assured iCOGS array genotype data. Development dataset comprised 31,747 men. Validation dataset comprised 6,411 men.
Main outcome measures: PHS prediction of age of onset of aggressive PCa in validation set.
Results: In the independent validation set, PHS calculated from 54 SNPs was a highly significant predictor of age at diagnosis of aggressive PCa (z=11.2, p98th percentile) were compared to those with average PHS (30th-70th percentile), the hazard ratio for aggressive PCa was 2.9.
Conclusions:Polygenic hazard scores give personalized genetic risk estimates that predict for age of onset of aggressive PCa.
George D, Martini J-F, Staehler M, Motzer R, Magheli A, Escudier B, Gerletti P, Li S, Casey M, Laguerre B, Pandha Hardev, Pantuck A, Patel A, Lechuga M, Ravaud A (2018) Immune biomarkers predictive for disease-free survival with adjuvant sunitinib in high-risk locoregional renal cell carcinoma: from randomized phase III S-TRAC study, Clinical Cancer Research American Association for Cancer Research
Purpose: Adjuvant sunitinib therapy compared with placebo prolonged disease-free survival (DFS) in patients with locoregional high-risk renal cell carcinoma in the S-TRAC trial (ClinicalTrials.gov number, NCT00375674). A prospectively-designed exploratory analysis of tissue biomarkers was conducted to identify predictors of treatment benefit.
Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. DFS was compared between Results: Baseline characteristics were similar in patients with (n=191) and without (n=419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density e versus Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic renal cell carcinoma should also be further explored.
Experimental Design: Tissue blocks were used for immunohistochemistry (IHC) staining of PD-L1, CD4, CD8, and CD68. DFS was compared between Results: Baseline characteristics were similar in patients with (n=191) and without (n=419) IHC analysis. Among patients with IHC, longer DFS was observed in patients with tumor CD8+ T-cell density e versus Conclusions: Greater CD8+ T-cell density in tumor tissue was associated with longer DFS with sunitinib but not placebo, suggesting predictive treatment effect utility. Further independent cohort validation studies are warranted. The prognostic value of PD-L1 expression in primary tumors from patients with high-risk non-metastatic renal cell carcinoma should also be further explored.
Khan Aadil A., Paget James T., McLaughlin Martin, Kyula Joan N., Wilkinson Michelle J., Pencavel Timothy, Mansfield David, Roulstone Victoria, Seth Rohit, Halle Martin, Somaiah Navita, Boult Jessica K. R., Robinson Simon P., Pandha Hardev, Vile Richard G., Melcher Alan A., Harris Paul A., Harrington Kevin J. (2018) Genetically modified lentiviruses that preserve microvascular function protect against late radiation damage in normal tissues, Science Translational Medicine 10 (425) American Association for the Advancement of Science
Improvements in cancer survival mean that long-term toxicities, which contribute to the morbidity of cancer survivorship, are being increasingly recognized. Late adverse effects (LAEs) in normal tissues after radiotherapy (RT) are characterized by vascular dysfunction and fibrosis causing volume loss and tissue contracture, for example, in the free flaps used for immediate breast reconstruction after mastectomy. We evaluated the efficacy of lentivirally delivered superoxide dismutase 2 (SOD2) overexpression and connective tissue growth factor (CTGF) knockdown by short hairpin RNA in reducing the severity of LAEs in an animal model of free flap LAEs. Vectors were delivered by intra-arterial injection, ex vivo, to target the vascular compartment. LVSOD2 and LVshCTGF monotherapy before irradiation resulted in preservation of flap volume or reduction in skin contracture, respectively. Flaps transduced with combination therapy experienced improvements in both volume loss and skin contracture. Both therapies reduced the fibrotic burden after irradiation. LAEs were associated with impaired vascular perfusion, loss of endothelial permeability, and stromal hypoxia, which were all reversed in the treatment model. Using a tumor recurrence model, we showed that SOD2 overexpression in normal tissues did not compromise the efficacy of RT against tumor cells but appeared to enhance it. LVSOD2 and LVshCTGF combination therapy by targeted, intravascular delivery reduced LAE severities in normal tissues without compromising the efficacy of RT and warrants translational evaluation as a free flap?targeted gene therapy.
Comins C, Simpson Guy, Rogers William, Relph Kate, Harrington K, Melcher A, Roulestone V, Kyula J, Pandha Hardev (2018) Synergistic anti-tumour effects of rapamycin and oncolytic reovirus, Cancer Gene Therapy 25 pp. 148-160 Nature Publishing Group
There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent,Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anti-cancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an anti-reovirus neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin, However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic anti-tumour efficacy of reovirus and rapamycin combination.
Morgan R, Pandha HS (2007) Antagonism of HOX/PBX dimer formation blocks the in vivo proliferation of melanoma, Cancer Research 67 (12) pp. 5806-5813 American Association for Cancer Research
Schumacher Fredrick R., Al Olama Ali Amin, Berndt Sonja I., Benlloch Sara, Ahmed Mahbubl, Saunders Edward J., Dadaev Tokhir, Leongamornlert Daniel, Anokian Ezequiel, Cieza-Borrella Clara, Goh Chee, Brook Mark N., Sheng Xin, Fachal Laura, Dennis Joe, Tyrer Jonathan, Muir Kenneth, Lophatananon Artitaya, Stevens Victoria L., Gapstur Susan M., Carter Brian D., Tangen Catherine M., Goodman Phyllis J., Thompson Ian M., Batra Jyotsna, Chambers Suzanne, Moya Leire, Clements Judith, Horvath Lisa, Tilley Wayne, Risbridger Gail P., Gronberg Henrik, Aly Markus, Nordström Tobias, Pharoah Paul, Pashayan Nora, Schleutker Johanna, Tammela Teuvo L. J., Sipeky Csilla, Auvinen Anssi, Albanes Demetrius, Weinstein Stephanie, Wolk Alicja, Håkansson Niclas, West Catharine M. L., Dunning Alison M., Burnet Neil, Mucci Lorelei A., Giovannucci Edward, Andriole Gerald L., Cussenot Olivier, Cancel-Tassin Géraldine, Koutros Stella, Beane Freeman Laura E., Sorensen Karina Dalsgaard, Orntoft Torben Falck, Borre Michael, Maehle Lovise, Grindedal Eli Marie, Neal David E., Donovan Jenny L., Hamdy Freddie C., Martin Richard M., Travis Ruth C., Key Tim J., Hamilton Robert J., Fleshner Neil E., Finelli Antonio, Ingles Sue Ann, Stern Mariana C., Rosenstein Barry S., Kerns Sarah L., Ostrer Harry, Lu Yong-Jie, Zhang Hong-Wei, Feng Ninghan, Mao Xueying, Guo Xin, Wang Guomin, Sun Zan, Giles Graham G., Southey Melissa C., MacInnis Robert J., FitzGerald Liesel M., Kibel Adam S., Drake Bettina F., Vega Ana, Gómez-Caamaño Antonio, Szulkin Robert, Eklund Martin, Kogevinas Manolis, Llorca Javier, Castaño-Vinyals Gemma, Penney Kathryn L., Stampfer Meir, Park Jong Y., Sellers Thomas A., Lin Hui-Yi, Stanford Janet L., Cybulski Cezary, Wokolorczyk Dominika, Lubinski Jan, Ostrander Elaine A., Geybels Milan S., Nordestgaard Børge G., Nielsen Sune F., Weischer Maren, Bisbjerg Rasmus, Røder Martin Andreas, Iversen Peter, Brenner Hermann, Cuk Katarina, Holleczek Bernd, Maier Christiane, Luedeke Manuel, Schnoeller Thomas, Kim Jeri, Logothetis Christopher J., John Esther M., Teixeira Manuel R., Paulo Paula, Cardoso Marta, Neuhausen Susan L., Steele Linda, Ding Yuan Chun, De Ruyck Kim, De Meerleer Gert, Ost Piet, Razack Azad, Lim Jasmine, Teo Soo-Hwang, Lin Daniel W., Newcomb Lisa F., Lessel Davor, Gamulin Marija, Kulis Tomislav, Kaneva Radka, Usmani Nawaid, Singhal Sandeep, Slavov Chavdar, Mitev Vanio, Parliament Matthew, Claessens Frank, Joniau Steven, Van den Broeck Thomas, Larkin Samantha, Townsend Paul A., Aukim-Hastie Claire, Dominguez Manuela Gago, Castelao Jose Esteban, Martinez Maria Elena, Roobol Monique J., Jenster Guido, van Schaik Ron H. N., Menegaux Florence, Truong Thérèse, Koudou Yves Akoli, Xu Jianfeng, Khaw Kay-Tee, Cannon-Albright Lisa, Pandha Hardev, Michael Agnieszka, Thibodeau Stephen N., McDonnell Shannon K., Schaid Daniel J., Lindstrom Sara, Turman Constance, Ma Jing, Hunter David J., Riboli Elio, Siddiq Afshan, Canzian Federico, Kolonel Laurence N., Le Marchand Loic, Hoover Robert N., Machiela Mitchell J., Cui Zuxi, Kraft Peter, Amos Christopher I., Conti David V., Easton Douglas F., Wiklund Fredrik, Chanock Stephen J., Henderson Brian E., Kote-Jarai Zsofia, Haiman Christopher A., Eeles Rosalind A. (2018) Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci, Nature Genetics 50 (7) pp. 928-936 Nature Publishing Group
Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P Â 5.0 × 10?8) with PrCa and one locus significantly associated with early-onset PrCa (d55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10?9; GÃC, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10?9; TÃG, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55?2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04?6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa.
Patel Poulam M., Ottensmeier Christian H., Mulatero Clive, Lorigan Paul, Plummer Ruth, Pandha Hardev, Elsheikh Somaia, Hadjimichael Efthymios, Villasanti Naty, Adams Sally E., Cunnell Michelle, Metheringham Rachael L., Brentville Victoria A., Machado Lee, Daniels Ian, Gijon Mohamed, Hannaman Drew, Durrant Lindy G. (2018) Targeting gp100 and TRP-2 with a DNA vaccine: Incorporating T cell epitopes with a human IgG1 antibody induces potent T cell responses that are associated with favourable clinical outcome in a phase I/II trial, OncoImmunology 7 (6) e1433516 pp. e1433516-1-e1433516-15 Taylor & Francis
A DNA vaccine, SCIB1, incorporating two CD8 and two CD4 epitopes from TRP-2/gp100 was evaluated in patients with metastatic melanoma. Each patient received SCIB1 via intramuscular injection with electroporation. The trial was designed to find the safest dose of SCIB1 which induced immune/clinical responses in patients with or without tumour. Fifteen patients with tumor received SCIB1 doses of 0.4-8 mg whilst 20 fully-resected patients received 2?8 mg doses. Twelve patients elected to continue immunization every 3 months for up to 39 months. SCIB1 induced dose-dependent T cell responses in 88% of patients with no serious adverse effects or dose limiting toxicities. The intensity of the T cell responses was significantly higher in patients receiving 4 mg doses without tumor when compared to those with tumor (p  0.01). In contrast, patients with tumor showed a significantly higher response to the 8 mg dose than the 4 mg dose (p  0.03) but there was no significant difference in the patients without tumor. One of 15 patients with measurable disease showed an objective tumor response and 7/15 showed stable disease. 5/20 fully-resected patients have experienced disease recurrence but all remained alive at the cut-off date with a median observation time of 37 months. A positive clinical outcome was associated with MHC-I and MHC-II expression on tumors prior to therapy (p = 0.027).
We conclude that SCIB1 is well tolerated and stimulates potent T cell responses in melanoma patients. It deserves further evaluation as a single agent adjuvant therapy or in combination with checkpoint inhibitors in advanced disease.
Acute myeloid leukaemia (AML) is a disorder characterised by the accumulation of blast cells or progenitors of one of several non-lymphoid haematopoietic cell lineages and is classified into two types: primary and secondary. HOX genes are over-expressed in both AML and other cancers. This over-expression is associated with an intermediate/unfavourable cytogenetic subset of AML. Although HOX over-expression is a common feature of AML, conventional knockout methods have failed to fully evaluate their functions due to their functional redundancy. We have applied an alternative approach by using a synthetic peptide called HXR9 to antagonise the interaction between HOX proteins and their cofactor PBX, which interacts with HOX proteins in groups 1-10.
AML cell lines derived from different AML types express different subsets of HOX genes at different levels due to the heterogeneity of AML. It is showed for the first time that targeting the HOX-PBX interaction using HXR9 led to cell death of the tested AML cell lines. This cell death did not appear to be through apoptosis, as there were no signs of the caspase activation and nuclear fragmentation. Likewise, there was also no activation of key necrotic markers such as cypD and PARP1. Instead, cell death involved, at least in part, the expression of c-FOS and p21 in p53-independentmanner. In addition, HXR9 caused cell death in MEK/ERK and p38 independent pathways, but the JNK pathway exerted a resistant effect in K562 cells. It was found that inhibiting the Ca2+ downstream mediators CaM, PKC and HO-1 significantly sensitised tested AML cell lines to HXR9. Taken together, these findings indicate a novel cell death pathway in AML cells. In vivo modelling also showed that HXR9 could delay tumour growth in a mouse model of AML.
AML cell lines derived from different AML types express different subsets of HOX genes at different levels due to the heterogeneity of AML. It is showed for the first time that targeting the HOX-PBX interaction using HXR9 led to cell death of the tested AML cell lines. This cell death did not appear to be through apoptosis, as there were no signs of the caspase activation and nuclear fragmentation. Likewise, there was also no activation of key necrotic markers such as cypD and PARP1. Instead, cell death involved, at least in part, the expression of c-FOS and p21 in p53-independentmanner. In addition, HXR9 caused cell death in MEK/ERK and p38 independent pathways, but the JNK pathway exerted a resistant effect in K562 cells. It was found that inhibiting the Ca2+ downstream mediators CaM, PKC and HO-1 significantly sensitised tested AML cell lines to HXR9. Taken together, these findings indicate a novel cell death pathway in AML cells. In vivo modelling also showed that HXR9 could delay tumour growth in a mouse model of AML.
Abstract:
Background:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid cancer with 5-year survival rates approaching a dismal 5%. Novel therapeutic targets need to be identified thus aiding and assisting the design of treatments which will improve survival rates that have not changed in the last 30 years. Of particular interest are homeobox (HOX) genes, a set of 39 evolutionarily conserved transcription factors involved in embryonic antero-posterior patterning. Although expressed in development, HOX genes have been found to be re-expressed and indeed dysregulated in several types of cancer including lung, breast, ovarian and renal neoplasia. Limited research has been undertaken on the dysregulation of HOX genes in PDAC. HOX genes can be antagonised using HXR9, a peptide which competitively inhibits the interaction between HOX genes and their co-factor PBX, subsequently preventing HOX genes to fulfill their role of transcription factors.
Cancer-specific tumour-modelling is fundamental to drug testing. There are few animal models that recapitulate the unique tumour architecture and molecular signature of PDAC, particularly the desmoplastic reaction characteristic of this malignancy. The chorioallantoic membrane (CAM) assay, an in ovo model that utilises the immunologically naive properties of the developing chick embryo to grow a solid tumour derived from pancreatic cancer cell lines. The CAM model is not widely used in pancreatic cancer research and more work is needed to evaluate it?s efficacy for tumour remodelling and subsequent drug testing.
We have found that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. In order to establish the CAM model as appropriate for drug testing in this context, we assessed whether the mitogen-activated protein kinases (MAPK) pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Global gene expression was also carried out to determine genetic changes between cells grown in vitro and cells in a tumour microenvironment in the CAM model.
Experimental design
We investigated whether there is a signature HOX gene profile unique to this disease. We measured HOX gene expression by RT-PCR in four well-described pancreatic cancer cell lines. HOX gene expression was also measured in commercially obtained RNA and snap-frozen pancreatic cancer tissue from surgical resections. The CAM model was set up by grafting 4 pancreatic cancer cell lines and tumour architecture and molecular signature was evaluated by H&E staining and IHC. Gene expression was assessed by microarray analysis to compare global gene expression in cell-lines and CAM tumours and conservation of mitogen-activated protein kinases (MAPK) pathway was addressed by western blotting. HOX gene expression was measured by RT-PCR in both cell lines and CAM tumours. Finally, the efficacy of HRX9 was measured by generating IC50s using MTS and LDH assays. Levels of apoptosis were measured in vitro using Annexin-V-PE assay and in vivo by cleaved-caspase activation, assessed by IHC.
Results:
We found that HOX gene expression was elevated in tumour samples compared with normal tissue and in particular a significantly higher expression of HOXA13 in PDAC samples compared with normal pancreas. This was confirmed at the protein level by Immunohistochemistry (IHC). We also showed that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. Results showed that MAPK pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Cleaved-caspase activation also supports the hypothesis that tumour cells are driven into apoptosis upon HXR9 treatment.
Conclusions
HOX gene expression is highly dys-regulated in pancreatic cancer and more work is need to individually evaluate HOX genes on interest highlighted in this s
Background:
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of solid cancer with 5-year survival rates approaching a dismal 5%. Novel therapeutic targets need to be identified thus aiding and assisting the design of treatments which will improve survival rates that have not changed in the last 30 years. Of particular interest are homeobox (HOX) genes, a set of 39 evolutionarily conserved transcription factors involved in embryonic antero-posterior patterning. Although expressed in development, HOX genes have been found to be re-expressed and indeed dysregulated in several types of cancer including lung, breast, ovarian and renal neoplasia. Limited research has been undertaken on the dysregulation of HOX genes in PDAC. HOX genes can be antagonised using HXR9, a peptide which competitively inhibits the interaction between HOX genes and their co-factor PBX, subsequently preventing HOX genes to fulfill their role of transcription factors.
Cancer-specific tumour-modelling is fundamental to drug testing. There are few animal models that recapitulate the unique tumour architecture and molecular signature of PDAC, particularly the desmoplastic reaction characteristic of this malignancy. The chorioallantoic membrane (CAM) assay, an in ovo model that utilises the immunologically naive properties of the developing chick embryo to grow a solid tumour derived from pancreatic cancer cell lines. The CAM model is not widely used in pancreatic cancer research and more work is needed to evaluate it?s efficacy for tumour remodelling and subsequent drug testing.
We have found that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. In order to establish the CAM model as appropriate for drug testing in this context, we assessed whether the mitogen-activated protein kinases (MAPK) pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Global gene expression was also carried out to determine genetic changes between cells grown in vitro and cells in a tumour microenvironment in the CAM model.
Experimental design
We investigated whether there is a signature HOX gene profile unique to this disease. We measured HOX gene expression by RT-PCR in four well-described pancreatic cancer cell lines. HOX gene expression was also measured in commercially obtained RNA and snap-frozen pancreatic cancer tissue from surgical resections. The CAM model was set up by grafting 4 pancreatic cancer cell lines and tumour architecture and molecular signature was evaluated by H&E staining and IHC. Gene expression was assessed by microarray analysis to compare global gene expression in cell-lines and CAM tumours and conservation of mitogen-activated protein kinases (MAPK) pathway was addressed by western blotting. HOX gene expression was measured by RT-PCR in both cell lines and CAM tumours. Finally, the efficacy of HRX9 was measured by generating IC50s using MTS and LDH assays. Levels of apoptosis were measured in vitro using Annexin-V-PE assay and in vivo by cleaved-caspase activation, assessed by IHC.
Results:
We found that HOX gene expression was elevated in tumour samples compared with normal tissue and in particular a significantly higher expression of HOXA13 in PDAC samples compared with normal pancreas. This was confirmed at the protein level by Immunohistochemistry (IHC). We also showed that the CAM model is suitable for drug testing as it recapitulates the architecture and molecular signature of PDAC. Results showed that MAPK pathway was conserved, due to the high frequency of mutational activation of the KRAS gene in this cancer. Cleaved-caspase activation also supports the hypothesis that tumour cells are driven into apoptosis upon HXR9 treatment.
Conclusions
HOX gene expression is highly dys-regulated in pancreatic cancer and more work is need to individually evaluate HOX genes on interest highlighted in this s
McGrath Sophie Elena, Annels Nicola, Madhuri Thumuluru K, Taylor Anil, Butler-Manuel Simon A., Morgan Richard, Pandha Hardev, Michael Agnieszka (2018) A novel Biomarker in epithelial ovarian cancer, BMC Cancer 18 943 BMC
BACKGROUND:
Epithelial ovarian cancer is a common malignancy, with no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We evaluated the expression of EN2 in Epithelial ovarian cancer, and reviewed its role as a biomarker.
METHODS
We evaluated 8 Epithelial ovarian cancer cell lines, along with >100 surgical specimens from the Royal Surrey County Hospital (2009-2014). In total, 108 tumours and 5 normal tissue specimens were collected. En2 mRNA was evaluated by semi-quantitative RT-PCR. Histological sub-type, and platinum-sensitive/-resistant status were compared. Protein expression was assessed in cell lines (immunofluorescence), and in >150 tumours (immunohistochemistry).
RESULTS
En2 mRNA expression was elevated in serous ovarian tumours compared with normal ovary (p CONCLUSION
The EN2 transcription factor is a novel ovarian cancer biomarker. It demonstrates prognostic value, correlating with worse Overall Survival and Progression-free Survival. It is hoped that further work will validate its use as a biomarker, and provide insight into the role of EN2 in the development, progression and spread of ovarian cancer.
Epithelial ovarian cancer is a common malignancy, with no clinically approved diagnostic biomarker. Engrailed-2 (EN2) is a homeodomain-containing transcription factor, essential during embryological neural development, which is dysregulated in several cancer types. We evaluated the expression of EN2 in Epithelial ovarian cancer, and reviewed its role as a biomarker.
METHODS
We evaluated 8 Epithelial ovarian cancer cell lines, along with >100 surgical specimens from the Royal Surrey County Hospital (2009-2014). In total, 108 tumours and 5 normal tissue specimens were collected. En2 mRNA was evaluated by semi-quantitative RT-PCR. Histological sub-type, and platinum-sensitive/-resistant status were compared. Protein expression was assessed in cell lines (immunofluorescence), and in >150 tumours (immunohistochemistry).
RESULTS
En2 mRNA expression was elevated in serous ovarian tumours compared with normal ovary (p CONCLUSION
The EN2 transcription factor is a novel ovarian cancer biomarker. It demonstrates prognostic value, correlating with worse Overall Survival and Progression-free Survival. It is hoped that further work will validate its use as a biomarker, and provide insight into the role of EN2 in the development, progression and spread of ovarian cancer.
Annels Nicola, Arif Mehreen, Simpson Guy, Denyer Mick, Moller-Levet Carla, Mansfield David, Butler Rachel, Shafren Darren, Au Gough, Knowles Margaret, Harrington Kevin, Vile Richard, Melcher Alan, Pandha Hardev (2018) Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus, Molecular Therapy - Oncolytics 9 pp. 1-12 Elsevier
As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-¼m precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer.
Matejcic Marco, Saunders Edward J, Dadaev Tokhir, Brook Mark N, Wang Kan, Sheng Xin, Al Olama Ali Amin, Schumacher Fredrick R, Ingles Sue A, Govindasami Koveela, Benlloch Sara, Berndt Sonja I, Albanes Demetrius, Koutros Stella, Muir Kenneth, Stevens Victoria L, Gapstur Susan M, Tangen Catherine M, Batra Jyotsna, Clements Judith, Gronberg Henrik, Pashayan Nora, Schleutker Johanna, Wolk Alicja, West Catharine, Mucci Lorelei, Kraft Peter, Cancel-Tassin Géraldine, Sorensen Karina D, Maehle Lovise, Grindedal Eli M, Strom Sara S, Neal David E, Hamdy Freddie C, Donovan Jenny L, Travis Ruth C, Hamilton Robert J, Rosenstein Barry, Lu Yong-Jie, Giles Graham G, Kibel Adam S, Vega Ana, Bensen Jeanette T, Kogevinas Manolis, Penney Kathryn L, Park Jong Y, Stanford Janet L, Cybulski Cezary, Nordestgaard Børge G, Brenner Hermann, Maier Christiane, Kim Jeri, Teixeira Manuel R, Neuhausen Susan L, De Ruyck Kim, Razack Azad, Newcomb Lisa F, Lessel Davor, Kaneva Radka, Usmani Nawaid, Claessens Frank, Townsend Paul A, Dominguez Manuela G, Roobol Monique J, Menegaux Florence, Khaw Kay-Tee, Cannon-Albright Lisa A, Pandha Hardev, Thibodeau Stephen N, Schaid Daniel J, Wiklund Fredrik, Chanock Stephen J, Easton Douglas F, Eeles Rosalind A, Kote-Jarai Zsofia, Conti David V, Haiman Christopher A (2018) Germline variation at 8q24 and prostate cancer risk in men of European ancestry, Nature Communications 9 4616 Nature Research
Chromosome 8q24 is a susceptibility locus for multiple cancers, including prostate cancer. Here we combine genetic data across the 8q24 susceptibility region from 71,535 prostate cancer cases and 52,935 controls of European ancestry to define the overall contribution of germline variation at 8q24 to prostate cancer risk. We identify 12 independent risk signals for prostate cancer (p
Rogers William (2018) Profiling and targeting HOX-PBX dimers in adult and paediatric glioblastoma as a novel therapy.,
HOX genes encode a family of transcription factors that play an essential role in embryonic patterning during foetal development. These genes are reported to be aberrantly expressed in numerous cancers, including glioblastoma (GBM). Previous research indicates that HOX genes are overexpressed in GBM tumours compared to normal human astrocytes (NHA). Three Amino Acid Loop Extension Homeobox (TALE) proteins act as important co-factors for HOX proteins, modulating their binding affinities to genomic targets. TALE members Pre-B-cell leukaemia homeobox (PBX) 1-4, bind anterior HOX proteins, facilitating cellular entry, while also limiting their degradation. HXR9, a small hexapeptide drug, has previously been shown to inhibit HOX-PBX dimers, causing rapid cell death in numerous solid and haemopoietic malignancies both in vitro and in vivo. HTL00-1 is a 2nd generation peptide based on HXR9, while ICT9119 is a small molecular inhibitor with the same binding site as the peptide inhibitors.
We found clear evidence of overexpression of both HOX and TALE genes, in both adult and paediatric GBM cell lines. A further elevation in expression of these genes was visible in GBM cancer stem cells (CSCs). Normal adult brain tissue expressed low to undetectable levels of HOX genes, while paediatric brains expressed high levels between 0-4 years of age, before dramatically reducing from ages 5 onwards. HOX-PBX inhibitors are shown to be both cytostatic and cytotoxic when used to treat adult and paediatric GBM cells both in vitro and in vivo. GBM CSCs were more sensitive to HOX-PBX inhibition, alluding to their increased reliance on these genes. HTL00-1 and ICT9119 were shown to provide improved pharmacological effects compared to their predecessor HXR9. All HOX-PBX inhibitors cause apoptosis through induction of Fos Proto-Oncogene AP-1 Transcription Factor Subunit (C-Fos) expression, which results in the dimerization of C-Fos and Jun Proto-Oncogene AP-1 Transcription Factor Subunit (C-Jun) to form the Activator protein 1 (AP-1) complex. This directly and indirectly represses B-cell lymphoma 2 (Bcl-2) expression leading to the release, and subsequent cleavage of caspase 3 and 7. This triggers the caspase cascade that concludes with cellular apoptosis.
Radiotherapy (RT), combined with ICT9119 treatment proved highly synergistic in terms of cell kill when applied in combination when cancer cells were exposed to RT 24 hours prior to ICT9119. When ICT9119 was delivered 24 hours prior to RT antagonistic effects were observed. Attempts to identify the molecular mechanisms behind differing sequential treatment outcomes proved inconclusive. However, our work did suggest a mixture of cell cycle sequestration, C-Jun induction and the opposing effects of dual specific phosphatase 1 (DUSP1) and Mitogen-activated protein kinases (MAPK) were at least partly involved.
This study highlights the important role of HOX genes in paediatric and adult gliomas, the potential utility of HOX/TALE gene expression in the identification of CSC population in patients and potential for HOX-PBX inhibition as a highly targeted effective treatment for adult and paediatric GBM patients. This treatment can be administered in the form of a peptide, as in HXR9 or HTL00-1, or as a small molecular agent in the form of ICT9119, either as single agents, or in combination with RT. HOX-PBX disruption as described in this thesis could potentially be moved rapidly into the clinic, in an area of very high unmet need.
We found clear evidence of overexpression of both HOX and TALE genes, in both adult and paediatric GBM cell lines. A further elevation in expression of these genes was visible in GBM cancer stem cells (CSCs). Normal adult brain tissue expressed low to undetectable levels of HOX genes, while paediatric brains expressed high levels between 0-4 years of age, before dramatically reducing from ages 5 onwards. HOX-PBX inhibitors are shown to be both cytostatic and cytotoxic when used to treat adult and paediatric GBM cells both in vitro and in vivo. GBM CSCs were more sensitive to HOX-PBX inhibition, alluding to their increased reliance on these genes. HTL00-1 and ICT9119 were shown to provide improved pharmacological effects compared to their predecessor HXR9. All HOX-PBX inhibitors cause apoptosis through induction of Fos Proto-Oncogene AP-1 Transcription Factor Subunit (C-Fos) expression, which results in the dimerization of C-Fos and Jun Proto-Oncogene AP-1 Transcription Factor Subunit (C-Jun) to form the Activator protein 1 (AP-1) complex. This directly and indirectly represses B-cell lymphoma 2 (Bcl-2) expression leading to the release, and subsequent cleavage of caspase 3 and 7. This triggers the caspase cascade that concludes with cellular apoptosis.
Radiotherapy (RT), combined with ICT9119 treatment proved highly synergistic in terms of cell kill when applied in combination when cancer cells were exposed to RT 24 hours prior to ICT9119. When ICT9119 was delivered 24 hours prior to RT antagonistic effects were observed. Attempts to identify the molecular mechanisms behind differing sequential treatment outcomes proved inconclusive. However, our work did suggest a mixture of cell cycle sequestration, C-Jun induction and the opposing effects of dual specific phosphatase 1 (DUSP1) and Mitogen-activated protein kinases (MAPK) were at least partly involved.
This study highlights the important role of HOX genes in paediatric and adult gliomas, the potential utility of HOX/TALE gene expression in the identification of CSC population in patients and potential for HOX-PBX inhibition as a highly targeted effective treatment for adult and paediatric GBM patients. This treatment can be administered in the form of a peptide, as in HXR9 or HTL00-1, or as a small molecular agent in the form of ICT9119, either as single agents, or in combination with RT. HOX-PBX disruption as described in this thesis could potentially be moved rapidly into the clinic, in an area of very high unmet need.
Kostalas Marcos (2019) Evaluation of the effects of oncolytic vaccinia virus on colorectal liver metastases in cell lines and in organotypic cultures.,
Vaccinia virus is one of several live viruses currently being evaluated in clinical trials as cancer therapies. One oncolytic virus, T-VEC, is already in clinical use and is NICE approved for the treatment of melanoma.
We have investigated a genetically modified, Copenhagen strain vaccinia virus encoding the fusion suicide gene (FCU1) that is able to convert non-toxic fluorocytosine into the active compound fluorouracil. The mode of cell death attributed to vaccinia virus is variable and multiple modes have been implicated based on tumour type. Through our work with colorectal cancer cell lines we have established that this form of oncolytic vaccinia virus induces cell death through a predominant picture of apoptosis. Furthermore, assessment of its immunogenicity has found there to be an increase in markers of immunogenic cell death following infection with the virus.
We have developed an organotypic culture system in our laboratory which enables us to assess oncolytic viruses on ex vivo tissue. Treatment of organotypic cultures from colorectal liver metastases have shown that vaccinia virus successfully infects and replicates in the tumour tissue. A dose-response relationship was observed with the highest doses of virus exerting the most effect on tumour tissue. Assessment of the pro-drug activation system through the conversion of 5-fluorocytosine to 5-fluorouracil in supernatant showed a high percentage conversion, whilst immunohistochemical staining did show evidence of an improved effect with the pro-drug system compared with virus alone.
We have evaluated the combination of cavitational ultrasound and sulphur hexafluoride microbubbles to enhance infection with oncolytic virus. Our results have shown that this method enhances infection of organotypic cultures treated with oncolytic vaccinia virus. This has enabled the use of a lower dose of virus whilst maintaining the same effects in tissue as that of virus at higher doses. This finding has translational implications that may enhance the efficacy of systemically administered oncolytic vaccinia virus.
We have investigated a genetically modified, Copenhagen strain vaccinia virus encoding the fusion suicide gene (FCU1) that is able to convert non-toxic fluorocytosine into the active compound fluorouracil. The mode of cell death attributed to vaccinia virus is variable and multiple modes have been implicated based on tumour type. Through our work with colorectal cancer cell lines we have established that this form of oncolytic vaccinia virus induces cell death through a predominant picture of apoptosis. Furthermore, assessment of its immunogenicity has found there to be an increase in markers of immunogenic cell death following infection with the virus.
We have developed an organotypic culture system in our laboratory which enables us to assess oncolytic viruses on ex vivo tissue. Treatment of organotypic cultures from colorectal liver metastases have shown that vaccinia virus successfully infects and replicates in the tumour tissue. A dose-response relationship was observed with the highest doses of virus exerting the most effect on tumour tissue. Assessment of the pro-drug activation system through the conversion of 5-fluorocytosine to 5-fluorouracil in supernatant showed a high percentage conversion, whilst immunohistochemical staining did show evidence of an improved effect with the pro-drug system compared with virus alone.
We have evaluated the combination of cavitational ultrasound and sulphur hexafluoride microbubbles to enhance infection with oncolytic virus. Our results have shown that this method enhances infection of organotypic cultures treated with oncolytic vaccinia virus. This has enabled the use of a lower dose of virus whilst maintaining the same effects in tissue as that of virus at higher doses. This finding has translational implications that may enhance the efficacy of systemically administered oncolytic vaccinia virus.
Jennings Victoria A., Scott Gina B., Rose Ailsa M.S., Scott Karen J., Migneco Gemma, Keller Brian, Reilly Katrina, Donnelly Oliver, Peach Howard, Dewar Donald, Harrington Kevin J., Pandha Hardev, Samson Adel, Vile Richard G., Melcher Alan A., Errington-Mais Fiona (2019) Potentiating Oncolytic Virus-Induced Immune-Mediated Tumor Cell Killing Using Histone Deacetylase Inhibition, Molecular Therapy Elsevier
A clinical oncolytic herpes simplex virus (HSV) encoding granulocyte-macrophage colony-stimulating factor (GM-CSF), talimogene laherparepvec, causes regression of injected and non-injected melanoma lesions in patients and is now licensed for clinical use in advanced melanoma. To date, limited data are available regarding the mechanisms of human anti-tumor immune priming, an improved understanding of which could inform the development of future combination strategies with improved efficacy. This study addressed direct oncolysis and innate and adaptive human immune-mediated effects of a closely related HSV encoding GM-CSF (HSVGM-CSF) alone and in combination with histone deacetylase inhibition. We found that HSVGM-CSF supported activation of anti-melanoma immunity via monocyte-mediated type I interferon production, which activates NK cells, and viral maturation of immature dendritic cells (iDCs) into potent antigen-presenting cells for cytotoxic T lymphocyte (CTL) priming. Addition of the histone deacetylase inhibitor valproic acid (VPA) to HSVGM-CSF treatment of tumor cells increased viral replication, viral GM-CSF production, and oncolysis and augmented the development of anti-tumor immunity. Mechanistically, VPA increased expression of activating ligands for NK cell recognition and induced expression of tumor-associated antigens, supporting innate NK cell killing and CTL priming. These data support the clinical combination of talimogene laherparepvec with histone deacetylase inhibition to enhance oncolysis and anti-tumor immunity.
Annels Nicola E, Mansfield David, Arif Mehreen, Ballesteros-Merino Carmen, Simpson Guy R, Denyer Mick, Sandhu Sarbjinder S, Melcher Alan, Harrington Kevin J, Davies BronwYn, Au Gough, Grose Mark, Bagwan Izhar N, Fox Bernard A., Vile Richard G, Mostafid Hugh, Shafren Darren, Pandha Hardev (2019) Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21, Clinical Cancer Research American Association for Cancer Research
Purpose: The CANON (CAVATAK in NON-muscle invasive bladder cancer) study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer.
Experimental Design: Fifteen patients enrolled on this 'window of opportunity' phase 1 study, exposing primary bladder cancers to CAVATAK prior to surgery. The first nine patients received intravesical administration of monotherapy CAVATAK; in the second stage, six patients received CAVATAK with a sub-therapeutic dose of mitomycinC, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose. Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, anti-tumour activity and viral-induced changes in resected tissue.
Results: Clinical activity of CAVATAK was demonstrated by induction of tumour inflammation and haemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumour in one patient. Whether used alone or in combination with mitomycinC, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by up-regulating interferon-inducible genes including both immune checkpoint-inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines as well as induction of the innate activator RIG-I, compared to bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy.
Conclusions: The acceptable safety profile of CAVATAK, proof of viral targeting, replication and tumour cell death together with the virus-mediated increases in "immunological heat" within the tumour microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.
Zhao Fang, Olkhov-Mitsel Ekaterina, Kamdar Shivani, Jeyapala Renu, Garcia Julia, Hurst Rachel, Hanna Marcelino Yazbek, Mills Robert, Tuzova Alexandra V., O?Reilly Eve, Kelly Sarah, Cooper Colin, Brewer Daniel, Perry Antoinette S., Clark Jeremy, Fleshner Neil, Bapat Bharati, Cooper Colin, Bapat Bharati, Bristow Rob, Parker Chris, Mills Ian, Pandha Hardev, Whitaker Hayley, Neal David, Olivan Mireia, Leung Hing, Perry Antoinette, Sanda Martin, Schalken Jack (2018) A urine-based DNA methylation assay, ProCUrE, to identify clinically significant prostate cancer, Clinical Epigenetics 10 147 pp. 1-12
Background
Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer.
Prevention of unnecessary biopsies and overtreatment of indolent disease remains a challenge in the management of prostate cancer. Novel non-invasive tests that can identify clinically significant (intermediate-risk and high-risk) diseases are needed to improve risk stratification and monitoring of prostate cancer patients. Here, we investigated a panel of six DNA methylation biomarkers in urine samples collected post-digital rectal exam from patients undergoing prostate biopsy, for their utility to guide decision making for diagnostic biopsy and early detection of aggressive prostate cancer.
Results
We recruited 408 patients in risk categories ranging from benign to low-, intermediate-, and high-risk prostate cancer from three international cohorts. Patients were separated into 2/3 training and 1/3 validation cohorts. Methylation biomarkers were analyzed in post-digital rectal exam urinary sediment DNA by quantitative MethyLight assay and investigated for their association with any or aggressive prostate cancers.
We developed a Prostate Cancer Urinary Epigenetic (ProCUrE) assay based on an optimal two-gene (HOXD3 and GSTP1) LASSO model, derived from methylation values in the training cohort, and assessed ProCUrE?s diagnostic and prognostic ability for prostate cancer in both the training and validation cohorts.
ProCUrE demonstrated improved prostate cancer diagnosis and identification of patients with clinically significant disease in both the training and validation cohorts. Using three different risk stratification criteria (Gleason score, D?Amico criteria, and CAPRA score), we found that the positive predictive value for ProCUrE was higher (59.4?78%) than prostate specific antigen (PSA) (38.2?72.1%) for all risk category comparisons. ProCUrE also demonstrated additive value to PSA in identifying GS e 7 PCa compared to PSA alone (DeLong?s test p = 0.039), as well as additive value to the PCPT risk calculator for identifying any PCa and GS e 7 PCa (DeLong?s test p = 0.011 and 0.022, respectively).
Conclusions
ProCUrE is a promising non-invasive urinary methylation assay for the early detection and prognostication of prostate cancer. ProCUrE has the potential to supplement PSA testing to identify patients with clinically significant prostate cancer.
Müller Louise M. E., Holmes Matthew, Michael Joanne L., Scott Gina B., West Emma J., Scott Karen J., Parrish Christopher, Halliwell Kathryn, Stäble Sina, Jennings Victoria A., Cullen Matthew, McConnell Stewart, Langton Catherine, Tidswell Emma L., Shafren Darren, Samson Adel, Harrington Kevin J., Pandha Hardev, Ralph Christy, Kelly Richard J., Cook Gordon, Melcher Alan A., Errington-Mais Fiona (2019) Plasmacytoid dendritic cells orchestrate innate and adaptive anti-tumor immunity induced by oncolytic coxsackievirus A21, Journal for ImmunoTherapy of Cancer 7 164 pp. 1-16 BMC
Background
The oncolytic virus, coxsackievirus A21 (CVA21), has shown promise as a single agent in several clinical trials and is now being tested in combination with immune checkpoint blockade. Combination therapies offer the best chance of disease control; however, the design of successful combination strategies requires a deeper understanding of the mechanisms underpinning CVA21 efficacy, in particular, the role of CVA21 anti-tumor immunity. Therefore, this study aimed to examine the ability of CVA21 to induce human anti-tumor immunity, and identify the cellular mechanism responsible.
Methods
This study utilized peripheral blood mononuclear cells from i) healthy donors, ii) Acute Myeloid Leukemia (AML) patients, and iii) patients taking part in the STORM clinical trial, who received intravenous CVA21; patients receiving intravenous CVA21 were consented separately in accordance with local institutional ethics review and approval. Collectively, these blood samples were used to characterize the development of innate and adaptive anti-tumor immune responses following CVA21 treatment.
Results
An Initial characterization of peripheral blood mononuclear cells, collected from cancer patients following intravenous infusion of CVA21, confirmed that CVA21 activated immune effector cells in patients. Next, using hematological disease models which were sensitive (Multiple Myeloma; MM) or resistant (AML) to CVA21-direct oncolysis, we demonstrated that CVA21 stimulated potent anti-tumor immune responses, including: 1) cytokine-mediated bystander killing; 2) enhanced natural killer cell-mediated cellular cytotoxicity; and 3) priming of tumor-specific cytotoxic T lymphocytes, with specificity towards known tumor-associated antigens. Importantly, immune-mediated killing of both MM and AML, despite AML cells being resistant to CVA21-direct oncolysis, was observed. Upon further examination of the cellular mechanisms responsible for CVA21-induced anti-tumor immunity we have identified the importance of type I IFN for NK cell activation, and demonstrated that both ICAM-1 and plasmacytoid dendritic cells were key mediators of this response.
Conclusion
This work supports the development of CVA21 as an immunotherapeutic agent for the treatment of both AML and MM. Additionally, the data presented provides an important insight into the mechanisms of CVA21-mediated immunotherapy to aid the development of clinical biomarkers to predict response and rationalize future drug combinations.
Connell Shea P., Yazbek-Hanna Marcelino, McCarthy Frank, Hurst Rachel, Webb Martyn, Curley Helen, Walker Helen, Mills Rob, Ball Richard Y., Sanda Martin G., Pellegrini Kathryn L., Patil Dattatraya, Perry Antoinette S., Schalken Jack, Pandha Hardev, Whitaker Hayley, Dennis Nening, Stuttle Christine, Mills Ian G., Guldvik Ingrid, Parker Chris, Brewer Daniel S., Cooper Colin S., Clark Jeremy, Bapat Bharati, Bristow Rob, Doll Andreas, Clark Jeremy, Cooper Colin, Leung Hing, Mills Ian, Neal David, Olivan Mireia, Pandha Hardev, Perry Antoinette, Parker Chris, Sanda Martin, Schalken Jack, Whitaker Hayley (2019) A four-group urine risk classifier for predicting outcomes in patients with prostate cancer, BJU International Wiley
Objectives
To develop a risk classifier using urine?derived extracellular vesicle (EV)?RNA capable of providing diagnostic information on disease status prior to biopsy, and prognostic information for men on active surveillance (AS).
Patients and Methods
Post?digital rectal examination urine?derived EV?RNA expression profiles (n = 535, multiple centres) were interrogated with a curated NanoString panel. A LASSO?based continuation ratio model was built to generate four prostate urine risk (PUR) signatures for predicting the probability of normal tissue (PUR?1), D'Amico low?risk (PUR?2), intermediate?risk (PUR?3), and high?risk (PUR?4) prostate cancer. This model was applied to a test cohort (n = 177) for diagnostic evaluation, and to an AS sub?cohort (n = 87) for prognostic evaluation.
Results
Each PUR signature was significantly associated with its corresponding clinical category (P Â 0.001). PUR?4 status predicted the presence of clinically significant intermediate? or high?risk disease (area under the curve = 0.77, 95% confidence interval [CI] 0.70?0.84). Application of PUR provided a net benefit over current clinical practice. In an AS sub?cohort (n = 87), groups defined by PUR status and proportion of PUR?4 had a significant association with time to progression (interquartile range hazard ratio [HR] 2.86, 95% CI 1.83?4.47; P Â 0.001). PUR?4, when used continuously, dichotomized patient groups with differential progression rates of 10% and 60% 5 years after urine collection (HR 8.23, 95% CI 3.26?20.81; P Â 0.001).
Conclusion
Urine?derived EV?RNA can provide diagnostic information on aggressive prostate cancer prior to biopsy, and prognostic information for men on AS. PUR represents a new and versatile biomarker that could result in substantial alterations to current treatment of patients with prostate cancer.
Additional publications