Professor Hardev Pandha

Professor of Medical Oncology

Qualifications: MD PhD

Email:
Phone: Work: 01483 68 8602
Room no: 26 PGM 02

Office hours

Mon-Fri 9am-5pm.

Further information

Biography

 

MB ChB (Birm), FRACP, FRCP, PhD, CSST (Medical Oncology)

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.

Research Interests

Tumour Immunology

Urological Cancer

Gene Therapy

For further information, please visit our Cancer Research theme page.

Publications

Journal articles

  • 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, Wokołorczyk D, Kluźniak 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, United States: 46 (10), pp. 1103-1109.

    Abstract

    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 < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

  • 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, United States: 22 (10), pp. 1851-1863.

    Abstract

    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.

  • Kyula JN, Khan AA, Mansfield D, Karapanagiotou EM, Mclaughlin M, Roulstone V, Zaidi S, Pencavel T, Touchefeu Y, Seth R, Harrington KJ, Chen NG, Yu YA, Zhang Q, Szalay AA, Melcher AA, Vile RG, Pandha HS, Ajaz M. (2014) 'Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in BRAF mutant melanoma depends on JNK and TNF-α signaling'. Oncogene, 33 (13), pp. 1700-1712.

    Abstract

    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 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 BRAF/ BRAF mutant cell lines and this was associated with TNF-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in BRAF mutant tumors. © 2014 Macmillan Publishers Limited.

  • 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, England: 177 (2), pp. 428-438.

    Abstract

    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.

  • Jennings VA, Ilett EJ, Scott KJ, West EJ, Selby P, Errington-Mais F, Melcher AA, Vile R, Pandha H, Harrington K, Young A, Hall GD, Coffey M. (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.

    Abstract

    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, IFNα and TNFα) 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.

  • 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, United States: 20 (7), pp. 1925-1934.

    Abstract

    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).

  • Morgan R, Boxall A, Harrington KJ, Simpson GR, Michael A, Pandha HS. (2014) 'Targeting HOX transcription factors in prostate cancer.'. BMC Urol, England: 14

    Abstract

    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.

  • Kottke T, Boisgerault N, Diaz RM, Rommelfanger-Konkol D, Pulido J, Thompson J, Vile R, 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, 19 (12), pp. 1625-1631.

    Abstract

    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.

  • McGrath SE, Michael A, Morgan R, Pandha H. (2013) 'EN2: a novel prostate cancer biomarker.'. Biomark Med, England: 7 (6), pp. 893-901.

    Abstract

    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.

  • 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, Germany: 63 (2), pp. 175-183.

    Abstract

    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.

  • 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,

    Abstract

    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.

  • 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, United States: 134 (5), pp. 1091-1101.

    Abstract

    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 (IFNɣ, IL-12, IFNα and TNFα) 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.

  • Errico MC, Felicetti F, Bottero L, Mattia G, Boe A, Felli N, Petrini M, Bellenghi M, Carè A, Pandha HS, Morgan R, Calvaruso M, Tripodo C, Colombo MP. (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.

    Abstract

    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/PBX2→miR-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.

  • Comins C, Simpson GR, Relph K, Pandha H, Harrington KJ, Melcher A. (2013) 'Reoviral Therapy for Cancer: Strategies for Improving Antitumor Efficacy Using Radio- and Chemotherapy'. Gene Therapy of Cancer: Translational Approaches from Preclinical Studies to Clinical Implementation: Third Edition, , pp. 185-198.

    Abstract

    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.

  • Boisgerault N, Kottke T, Pulido J, Thompson J, Diaz RM, Rommelfanger-Konkol D, Embry A, Saenz D, Poeschla E, 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, 21 (8), pp. 1507-1516.

    Abstract

    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-IIα (TOPO-IIα) 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-IIα 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.

  • Donnelly O, Harrington K, Melcher A, Pandha H. (2013) 'Live viruses to treat cancer.'. J R Soc Med, England: 106 (8), pp. 310-314.

    Abstract

    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.

  • 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,

    Abstract

    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-IIα (TOPO-IIα) 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-IIα 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.

  • Morgan R, Javed S, Launchbury F, Pandha H, Bryan RT, James ND, Wallace DMA, Ward DG, Zeegers MP, Cheng KK, Hurst CD, Knowles MA. (2013) 'Expression of Engrailed-2 (EN2) protein in bladder cancer and its potential utility as a urinary diagnostic biomarker'. European Journal of Cancer, 49 (9), pp. 2214-2222.

    Abstract

    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.© 2013 Elsevier Ltd. All rights reserved.

  • Adair RA, Scott KJ, Fraser S, Errington-Mais F, Selby P, Cook GP, Vile R, Toogood G, Melcher AA, Pandha H, Coffey M, Harrington KJ. (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.

    Abstract

    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.

  • Roulstone V, Twigger K, Zaidi S, Pencavel T, Kyula JN, White C, McLaughlin M, Seth R, Karapanagiotou EM, Mansfield D, Harrington KJ, Coffey M, Nuovo G, Vile RG, Melcher AA, Pandha HS. (2013) 'Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy'. Gene Therapy, 20 (5), pp. 521-528.

    Abstract

    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.

  • Alharbi RA, Pandha HS, Morgan R, Pettengell R. (2013) 'The role of HOX genes in normal hematopoiesis and acute leukemia'. Leukemia, 27 (5), pp. 1000-1008.

    Abstract

    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. © 2013 Macmillan Publishers Limited All rights reserved.

  • 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-α signaling.'. Oncogene, England: 33 (13), pp. 1700-1712.

    Abstract

    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-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors.

  • McGrath SE, Michael A, Pandha H, Morgan R. (2013) 'Engrailed homeobox transcription factors as potential markers and targets in cancer.'. FEBS Lett, Netherlands: 587 (6), pp. 549-554.

    Abstract

    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 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.

    Abstract

    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.

  • Michael A, Relph K, Annels N, Pandha H. (2013) 'Prostate cancer vaccines.'. Expert Rev Vaccines, England: 12 (3), pp. 253-262.

    Abstract

    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.

  • 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, 26 (2), pp. 226-235.

    Abstract

    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.

  • Morgan R, Bryan RT, Javed S, Launchbury F, Zeegers MP, Cheng KK, James ND, Wallace DM, Hurst CD, Ward DG, Knowles MA, Pandha H. (2013) 'Expression of Engrailed-2 (EN2) protein in bladder cancer and its potential utility as a urinary diagnostic biomarker.'. Eur J Cancer,

    Abstract

    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.

  • Mansfield D, Pencavel T, Kyula JN, Zaidi S, Roulstone V, Karapanagiotou L, Khan AA, McLaughlin M, Touchefeu Y, Seth R, Harrington KJ, Thway K, Melcher AA, Vile RG, Pandha HS. (2013) 'Oncolytic Vaccinia virus and radiotherapy in head and neck cancer'. Oral Oncology, 49 (2), pp. 108-118.

    Abstract

    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.

  • 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, England: 3

    Abstract

    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.

  • 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,

    Abstract

    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.

  • Donnelly OG, Errington-Mais F, Steele L, Jennings V, Scott K, Bond J, Vile R, Selby P, Melcher AA, Hadac E, Russell S, Peach H, Phillips RM, Pandha H, Harrington K. (2013) 'Measles virus causes immunogenic cell death in human melanoma'. Gene Therapy, 20 (1), pp. 7-15.

    Abstract

    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.

  • Alharbi RA, Pettengell R, Pandha HS, Morgan R. (2012) 'The role of HOX genes in normal hematopoiesis and acute leukemia.'. Leukemia,

    Abstract

    The 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 genes targets and implications for therapy.Leukemia accepted article preview online, 5 December 2012; doi:10.1038/leu.2012.356.

  • Morgan R, Boxall A, Harrington KJ, Simpson GR, Gillett C, Michael A, Pandha HS. (2012) 'Targeting the HOX/PBX dimer in breast cancer.'. Breast Cancer Res Treat, Netherlands: 136 (2), pp. 389-398.

    Abstract

    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.

  • 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,

    Abstract

    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.

  • Morgan R, Boxall A, Simpson GR, Michael A, Pandha HS, Harrington KJ, Gillett C. (2012) 'Targeting the HOX/PBX dimer in breast cancer'. Breast Cancer Research and Treatment, 136 (2), pp. 389-398.

    Abstract

    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. © Springer Science+Business Media New York 2012.

  • Pandha H, Morgan R, Sorensen KD, Orntoft TF, Borre M, Hoyer S, Langley S. (2012) 'Urinary engrailed-2 (EN2) levels predict tumour volume in men undergoing radical prostatectomy for prostate cancer'. BJU International, 110 (6B)

    Abstract

    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 Âμg/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.

  • 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, England: 110 (6 Pt B), pp. E287-E292.

    Abstract

    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).

  • 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,

    Abstract

    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.

  • 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,

    Abstract

    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.

  • Donnelly O, Vile R, Pandha H, Harrington K, Melcher A. (2012) 'The hitchhiker's guide to virotherapy.'. Oncotarget, United States: 3 (8), pp. 735-736.
  • 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.

    Abstract

    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.

  • 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, United States: 4 (138)

    Abstract

    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.

  • 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.
  • 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, United States: 18 (7), pp. 2080-2089.

    Abstract

    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.

  • 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.
  • 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, United States: 1 (1), pp. 3-15.

    Abstract

    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 (IFNα) 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 IFNγ 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.

  • Pulido J, Kottke T, Thompson J, Galivo F, Diaz RM, Rommelfanger D, Ilett E, Vile R, Wongthida P, Selby P, Melcher A, Pease L, Pandha H, Harrington K. (2012) 'Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma'. Nature Biotechnology, 30 (4), pp. 337-343.

    Abstract

    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.

  • 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, Germany: 61 (1), pp. 1-7.

    Abstract

    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.

  • 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, England: 12

    Abstract

    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.

  • 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,

    Abstract

    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.

  • Metcalf S, Pandha HS, Morgan R. (2011) 'Antiangiogenic effects of zoledronate on cancer neovasculature.'. Future Oncol, England: 7 (11), pp. 1325-1333.

    Abstract

    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.

  • 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, United States: 19 (10), pp. 1802-1812.

    Abstract

    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.

  • 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,

    Abstract

    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.

  • 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, United States: 17 (7), pp. 854-859.

    Abstract

    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.

  • 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, England: 18 (7), pp. 478-488.

    Abstract

    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 <1% to ∼40% of cells transduced, depending on the cell line. Efficient Ad5EGFP transduction was associated mainly with higher levels of cell surface Coxsackie and adenovirus receptor (CAR) but not with expression of α(v)β(3) and α(v)β(5) integrins and was fiber dependent. Reduction of CAR by RNA interference resulted in a corresponding decrease in Ad5EGFP transduction. Pre-treatment of Ad5EGFP with blood coagulation Factor X increased virus entry even in the presence of low CAR levels generated by RNA interference, suggesting a potential alternative route of Ad5 entry into pancreatic cancer cells. Immunohistochemistry carried out on 188 pancreatic ductal adenocarcinomas and 68 matched controls showed that CAR was absent in 102 (54%) of adenocarcinomas, whereas moderate and strong staining was observed in 58 (31%) and 28 (15%) cases, respectively. Weak or absent CAR immunolabeling correlated with poor histological differentiation of pancreatic cancer. In normal tissue, strong immunolabeling was detected in islet cells and in the majority of inter- and intralobular pancreatic ducts.

  • 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,

    Abstract

    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-γ, TNF-α 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.

  • 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)
  • 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)
  • 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, United States: 17 (9), pp. 2767-2776.

    Abstract

    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.

  • 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.
  • 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 Article number ARTN 20
  • Kottke T, Ilett E, Thompson J, Diaz R, Vile R, Chester J, Selby P, Melcher A, Coffey M, Nuovo G, Pulido J, Mukhopadhyay D, Pandha H, Harrington K. (2011) 'Precise scheduling of chemotherapy primes VEGF-producing tumors for successful systemic oncolytic virotherapy'. Molecular Therapy, 19 (10), pp. 1802-1812.

    Abstract

    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.

  • 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.
  • Kelly ZL, Michael A, Butler-Manuel S, Pandha HS, Morgan RG. (2011) 'HOX genes in ovarian cancer'. Journal of Ovarian Research, 4 (1)

    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.

  • 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, England: 11

    Abstract

    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.

  • Gray S, Pandha HS, Michael A, Middleton G, Morgan R. (2011) 'HOX genes in pancreatic development and cancer.'. JOP, Italy: 12 (3), pp. 216-219.

    Abstract

    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.

  • 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.
  • Kelly ZL, Michael A, Butler-Manuel S, Pandha HS, Morgan RG. (2011) 'HOX genes in ovarian cancer.'. J Ovarian Res, England: 4

    Abstract

    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.

  • 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.
  • 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.
  • 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.
  • Annels NE, Denyer M, Pandha H. (2010) 'Increased Myeloid Derived Suppressor Cells in Advanced Prostate Cancer'. J IMMUNOTHER, 33 (8), pp. 890-891.
  • 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.
  • 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.
  • 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 Article number ARTN 486
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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)
  • 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.
  • 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.
  • 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 Article number ARTN 14
  • Morgan R, Plowright L, Harrington KJ, Michael A, Pandha HS. (2010) 'Targeting HOX and PBX transcription factors in ovarian cancer'. BMC CANCER, 10 Article number ARTN 89
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Pandha HS, Heinemann L, Simpson GR, Melcher A, Prestwich R, Errington F, Coffey M, Harrington KJ, Morgan R. (2009) 'Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma'. CLINICAL CANCER RESEARCH, 15 (19), pp. 6158-6166.
  • 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.
  • 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.
  • 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.
  • Pandha H, Melcher A, Harrington K, Vile R. (2009) 'Oncolytic Viruses: Time to Compare, Contrast, and Combine?'. MOLECULAR THERAPY, 17 (6), pp. 934-935.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Pandha H, Melcher A, Vile R, Harrington K. (2009) '5th international meeting on replicating oncolytic virus therapeutics Banff, Alberta, Canada, 18-22 March 2009'. Molecular Therapy, 17 (6), pp. 934-935.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, Netherlands: 19 (7), pp. e67-e69.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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)
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, New Zealand: 2, pp. 83-96.

    Abstract

    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.

  • 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.
  • 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.
  • 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.
  • 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.
  • Morgan R, Pirard PM, Shears L, Sohal J, Pettengell R, Pandha HS. (2007) 'Antagonism of HOX/PBX dimer formation blocks the in vivo proliferation of melanoma'. CANCER RESEARCH, 67 (12), pp. 5806-5813.
  • 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.
  • 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.
  • Dalgleish A, Pandha H, Hampton GM, Sikora K. (2007) 'Tumor antigens as surrogate markers and targets for therapy and vaccines'. ADVANCES IN CANCER RESEARCH, VOL 96, 96, pp. 175-190.
  • 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.
  • 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.
  • 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.
  • 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 Article number ARTN 51
  • Chowdhury S, Pandha H. (2006) 'Targeting renal cell carcinoma'. CLINICAL ONCOLOGY, 18 (7), pp. 511-512.
  • 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.
  • 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.

Conference papers

  • 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'. WILEY-BLACKWELL BJU INTERNATIONAL, Liverpool, ENGLAND: Annual Scientific Meeting of the British-Association-of-Urological-Surgeons (BAUS) 113, pp. 43-44.
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Washington, DC: 17th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 22, pp. S245-S245.
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Washington, DC: 17th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 22, pp. S200-S200.
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Washington, DC: 17th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 22, pp. S245-S245.
  • 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'. WILEY-BLACKWELL IMMUNOLOGY, Liverpool, ENGLAND: Annual Congress of the British-Society-for-Immunology 140, pp. 69-69.
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Salt Lake City, UT: 16th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 21, pp. S152-S152.
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Salt Lake City, UT: 16th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 21, pp. S7-S7.
  • 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'. WILEY-BLACKWELL BJU INTERNATIONAL, Manchester, ENGLAND: Annual Scientific Meeting of the British-Association-of-Urological-Surgeons (BAUS) 111, pp. 12-12.
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Salt Lake City, UT: 16th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 21, pp. S249-S249.
  • 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'. AMER ASSOC CANCER RESEARCH CANCER RESEARCH, Washington, DC: 104th Annual Meeting of the American-Association-for-Cancer-Research (AACR) 73 (8)
  • 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'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, North Bethesda, MD: 27th Annual Scientific Meeting of the Society-for-Immunotherapy-of-Cancer (SITC) 35 (9), pp. 775-775.
  • 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)'. OXFORD UNIV PRESS ANNALS OF ONCOLOGY, Vienna, AUSTRIA: 37th Congress of the European-Society-for-Medical-Oncology (ESMO) 23, pp. 292-293.
  • Kelly Z, Pandha H, Madhuri K, Morgan R, Michael A. (2012) 'HOX GENE EXPRESSION IN OVARIAN CANCER'. OXFORD UNIV PRESS ANNALS OF ONCOLOGY, Vienna, AUSTRIA: 37th Congress of the European-Society-for-Medical-Oncology (ESMO) 23, pp. 68-68.
  • Kelly Z, Pandha H, Morgan R, Michael A. (2012) 'HXR9 AND PARP INHIBITION -A NOVEL THERAPEUTIC IN OVARIAN CANCER'. OXFORD UNIV PRESS ANNALS OF ONCOLOGY, Vienna, AUSTRIA: 37th Congress of the European-Society-for-Medical-Oncology (ESMO) 23, pp. 325-325.
  • 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'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) 30 (15)
  • 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'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) 30 (15)
  • 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?'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Chicago, IL: 48th Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO) 30 (15)
  • 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'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, Philadelphia, PA: 15th Annual Meeting of the American-Society-of-Gene-and-Cell-Therapy (ASGCT) 20, pp. S268-S268.
  • 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, Chicago: ASCO (J Clin Oncol 29: 2011 (suppl; abstr e15528))

    Abstract

    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 (<10%) or absent in normal tissues. Out of the 67 ovarian cancer patients 20.9% (14/67) had antibodies against EN2 compared to 2.4% (1/42) of age-matched female controls. 4 of the identified EN2 epitopes were able to generate peptide specific cytotoxic T lymphocytes in the ovarian cancer patients tested. Conclusions: The over-expression and immunogenicity of EN2 in ovarian cancer makes it a credible antigen to exploit as a novel target for ovarian cancer immunotherapy. ž

  • 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), Chicago USA: ASCO

    Abstract

    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 ≤ 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 ≤ 70 y.o. and 24 (38.8%) were >70y.o. 2 patients (5%) of ≤70 and 5 (20%) of > 70y.o. were non-evaluable for response due to early treatment discontinuation. The response rate was 36% in ≤70y.o. and 21% in >70 y.o., stable disease (SD) was observed in 41% ≤70 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 ≤70 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 ≤70y.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 ≤70y.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.

  • 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'. WILEY-BLACKWELL BRITISH JOURNAL OF SURGERY, Royal Free Hosp, London, ENGLAND: Annual Meeting of the Society-of-Academic-and-Research-Surgeons 98 (6), pp. E2-E2.
  • 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'. WILEY-BLACKWELL BRITISH JOURNAL OF SURGERY, Royal Coll Surgery, Dublin, IRELAND: Annual Meeting of the Society-of-Academic-and-Research-Surgery 98, pp. 48-48.
  • Michael A, Zylstra J, Pandha H. (2011) 'The sun study-a biobank of sequential blood samples from patients with prostate cancer'. WILEY-BLACKWELL BRITISH JOURNAL OF SURGERY, Royal Coll Surgery, Dublin, IRELAND: Annual Meeting of the Society-of-Academic-and-Research-Surgery 98, pp. 50-50.
  • Binda E, Perez SM, Pandha H, Eberl M, Hayday A. (2010) 'Monitoring the immunological effects of bisphosphonates in different treatment scenarios'. WILEY-BLACKWELL PUBLISHING, INC IMMUNOLOGY, Liverpool, ENGLAND: Annual Congress of the British-Society-for-Immunology 131, pp. 117-117.
  • 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'. WILEY-BLACKWELL PUBLISHING, INC IMMUNOLOGY, Liverpool, ENGLAND: Annual Congress of the British-Society-for-Immunology 131, pp. 119-119.
  • Annels NE, Riley C, Bokaee S, Denyer M, Simpson GR, Pandha H. (2010) 'EN2: A Novel Immunotherapeutic Target for Melanoma'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, 33 (8), pp. 891-891.
  • 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'. ELSEVIER SCIENCE BV EUROPEAN UROLOGY SUPPLEMENTS, 9 (6), pp. 646-646.
  • 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), Chicago USA: ASCO

    Abstract

    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<0.001). Conclusions: Thus Engrailed-2 is a potential diagnostic marker for prostate cancer.

  • Ismail M, Morgan R, Davies J, Pandha H. (2009) 'Inhibition of the aquaporin water channels (AQPs) increases the sensitivity of DU145 cells to cryotherapy'. WILEY-BLACKWELL PUBLISHING, INC BJU INTERNATIONAL, Glasgow, SCOTLAND: Annual Meeting of the British-Association-of-Urological-Surgeons 103, pp. 21-21.
  • 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'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Orlando, FL: 45th Annual Meeting of the American-Society-of-Clinical-Oncology 27 (15)
  • 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'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Orlando, FL: 45th Annual Meeting of the American-Society-of-Clinical-Oncology 27 (15)
  • 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'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, Chicago, IL: 104th Annual Meeting of the American-Urological-Association 181 (4), pp. 189-190.
  • 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.'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, Chicago, IL: 104th Annual Meeting of the American-Urological-Association 181 (4), pp. 185-185.
  • 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'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, San Diego, CA: 23rd Annual Scientific Meeting of the International-Society-for-Biological-Therapy-of-Cancer 31 (9), pp. 952-952.
  • 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'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, San Diego, CA: 23rd Annual Scientific Meeting of the International-Society-for-Biological-Therapy-of-Cancer 31 (9), pp. 951-951.
  • 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'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, San Diego, CA: 23rd Annual Scientific Meeting of the International-Society-for-Biological-Therapy-of-Cancer 31 (9), pp. 951-952.
  • 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'. PERGAMON-ELSEVIER SCIENCE LTD EJC SUPPLEMENTS, Geneva, SWITZERLAND: 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 6 (12), pp. 97-98.
  • 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'. PERGAMON-ELSEVIER SCIENCE LTD EJC SUPPLEMENTS, Geneva, SWITZERLAND: 20th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics 6 (12), pp. 99-99.
  • 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'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, Orlando, FL: 103rd Annual Meeting of the American-Urological-Association 179 (4), pp. 48-48.
  • 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'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, Boston, MA: 22nd Annual Scientific Meeting of the International-Society-for-Biological-Therapy-of-Cancer 30 (8), pp. 891-891.
  • 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'. LIPPINCOTT WILLIAMS & WILKINS JOURNAL OF IMMUNOTHERAPY, Boston, MA: 22nd Annual Scientific Meeting of the International-Society-for-Biological-Therapy-of-Cancer 30 (8), pp. 887-887.
  • 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'. BLACKWELL PUBLISHING BJU INTERNATIONAL, Glasgow, SCOTLAND: Annual Meeting of the British-Association-of-Urological-Surgeons 99, pp. 47-48.
  • 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'. JOHN WILEY & SONS LTD JOURNAL OF PATHOLOGY, Manchester, ENGLAND: 190th Meeting of the Pathological-Society-of-Great-Britain-and-Ireland 210, pp. 2-2.
  • 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.'. AMER SOC CLINICAL ONCOLOGY JOURNAL OF CLINICAL ONCOLOGY, Atlanta, GA: 42nd Annual Meeting of the American-Society-of-Clinical-Oncology 24 (18), pp. 136S-136S.
  • 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.'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, Philadelphia, PA: AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics 11 (24), pp. 9005S-9006S.
  • 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.'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, Philadelphia, PA: AACR/NCI/EORTC International Conference on Molecular Targets and Cancer Therapeutics 11 (24), pp. 9106S-9107S.

Books

  • Pandha HS, Relph K, Harrington K. (2008) Treatment of Cancer 5th Edition Chapter Gene Therapy. 5th Edition.
  • Pandha HS, Harrington KJ, Vile RG. (2008) Viral Therapy of Cancer. John Wiley

Book chapters

  • Pandha HS, Harrington KJ, Vile RG. (2008) 'Poxviruses as immunomodulatory cancer therapeutics.'. in (ed.) Viral Therapy of Cancer

 

8 Book Chapters

 

Methods Mol Biol. 2009;542:551-64. Simpson GR, Coffin RS. Construction and characterization of an oncolytic HSV vector containing a fusogenic glycoprotein and prodrug activation for enhanced local tumor control.

 

Treatment of Cancer 5th Edition 2008. Edited by Pat Price Karol Sikora and Timothy Illidge.

Chapter: Gene Therapy Kate Relph, Kevin Harrington, Hardev Pandha.

 

Viral Therapy of Cancer. Ed K.J. Harrington, H.S. Pandha and R.G. Vile. Publish by John Wiley Ltd.(ISBN 978-0-470-01922-1).

Chapter: Adenoviruses. Kate Relph,

 

Chapter: Oncolytic herpes simplex viruses. Guy R. Simpson and Robert S. Coffin

 

Chapter: Poxviruses as immunomodulatory cancer therapeutics. Kevin J Harrington, Hardev S Pandha and Richard G Vile.

 

Comprehensive Textbook of Prostate Cancer, edited by Dr. Tewari,

Chapter: Presentation and symptomatology of prostate cancer Dr A Michael

Chapter: Prostate Immunotherapy Dr Nicola Annels

 

Training in Oncology, Oncology and Paliative Care (Manuscript in preparation) Oxford University Press. Michael A and Pandha H

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