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

  • 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.

  • 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.

  • 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.

  • 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.

  • 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.'. Elsevier 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.

  • 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.'. Nature Publishing Group 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.'. Springer 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, 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.'. Wiley-Blackwell 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).

  • 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.

  • 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 PUBLISHING GROUP 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.
  • 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.

  • 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.

  • 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.

  • 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.

  • 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.

  • 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 17 (5), pp. 1090-1098.
  • Kelly ZL, Michael A, Butler-Manuel S, Pandha HS, Morgan RG. (2011) 'HOX genes in ovarian cancer'. Springer 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.

  • 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.

  • 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'. BIOMED CENTRAL LTD MOLECULAR CANCER, 10 Article number ARTN 20
  • 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.
  • 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.

  • 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.

  • 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.
  • 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.'. Biomed Central 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.

  • 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 16 (22), pp. 5564-5572.
  • Annels NE, Denyer M, Pandha H. (2010) 'Increased Myeloid Derived Suppressor Cells in Advanced Prostate Cancer'. LIPPINCOTT WILLIAMS & WILKINS J IMMUNOTHER, 33 (8), pp. 890-891.
  • 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'. LIPPINCOTT WILLIAMS & WILKINS 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'. LIPPINCOTT WILLIAMS & WILKINS J IMMUNOTHER, 33 (8), pp. 897-897.
  • 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'. ACADEMIC PRESS INC ELSEVIER SCIENCE 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'. NATURE PUBLISHING GROUP 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'. BIOMED CENTRAL LTD BMC CANCER, 10 Article number ARTN 486
  • Michael A, Relph K, Pandha H. (2010) 'Emergence of potential biomarkers of response to anti-angiogenic anti-tumour agents'. WILEY-BLACKWELL INTERNATIONAL JOURNAL OF CANCER, 127 (6), pp. 1251-1258.
  • Lunt C, Barber N, Montgomery A, Kalsi V, Parker T, Michael A, Pandha H, Hindley R. (2010) 'CYTOREDUCTIVE NEPHRECTOMY IN THE TYROKINASE INHIBITOR ERA'. MARY ANN LIEBERT INC J ENDOUROL, 24, pp. A303-A303.
  • 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?'. NATURE PUBLISHING GROUP 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'. NATURE PUBLISHING GROUP 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'. NATURE PUBLISHING GROUP 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 16 (11), pp. 3067-3077.
  • 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'. AMER SOC CLINICAL INVESTIGATION INC 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'. ELSEVIER SCI LTD 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'. BIOMED CENTRAL LTD 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'. BIOMED CENTRAL LTD 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'. BENTHAM SCIENCE PUBL LTD 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'. THESCIENTIFICWORLD LTD THESCIENTIFICWORLDJOURNAL, 10, pp. 393-401.
  • 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'. AMER ASSOC IMMUNOLOGISTS JOURNAL OF IMMUNOLOGY, 183 (7), pp. 4312-4321.
  • 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'. MARY ANN LIEBERT INC HUMAN GENE THERAPY, 20 (10), pp. 1119-1132.
  • 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 15 (19), pp. 6158-6166.
  • 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'. ACADEMIC PRESS INC ELSEVIER SCIENCE CRYOBIOLOGY, 59 (2), pp. 207-213.
  • 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'. WILEY-BLACKWELL 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'. AMER ASSOC CANCER RESEARCH 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'. NATURE PUBLISHING GROUP 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?'. NATURE PUBLISHING GROUP MOLECULAR THERAPY, 17 (6), pp. 934-935.
  • 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'. ELSEVIER SCIENCE LONDON CLINICAL ONCOLOGY, 21 (4), pp. 363-364.
  • 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'. NATURE PUBLISHING GROUP GENE THERAPY, 16 (5), pp. 689-699.
  • 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'. ELSEVIER SCIENCE BV EUR UROL SUPPL, 8 (4), pp. 196-196.
  • Michael A, Syrigos K, Pandha H. (2009) 'Prostate cancer chemotherapy in the era of targeted therapy'. NATURE PUBLISHING GROUP 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'. WILEY-BLACKWELL PUBLISHING, INC 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)'. NATURE PUBLISHING GROUP 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.
  • 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'. NATURE PUBLISHING GROUP GENE THERAPY, 16 (1), pp. 78-92.
  • 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.
  • Yap TA, Brunetto A, Pandha H, Harrington K, de Bono JS. (2008) 'Reovirus therapy in cancer: has the orphan virus found a home?'. INFORMA HEALTHCARE 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'. AMER ASSOC CANCER RESEARCH 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'. AMER ASSOC CANCER RESEARCH 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'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, 180 (5), pp. 2196-2201.
  • 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.
  • 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 14 (21), pp. 7127-7137.
  • Prestwich RJ, Harrington KJ, Pandha HS, Vile RG, Melcher AA, Errington F. (2008) 'Oncolytic viruses: a novel form of immunotherapy'. EXPERT REVIEWS 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''. ELSEVIER SCIENCE LONDON 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'. NATURE PUBLISHING GROUP GENE THERAPY, 15 (18), pp. 1257-1270.
  • 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 14 (15), pp. 4915-4924.
  • Harrington KJ, Melcher A, Vassaux G, Pandha HS, Vile RG. (2008) 'Exploiting synergies between radiation and oncolytic viruses'. THOMSON SCIENTIFIC CURRENT OPINION IN MOLECULAR THERAPEUTICS, 10 (4), pp. 362-370.
  • 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'. NATURE PUBLISHING GROUP 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)'. AMER SOC CLINICAL ONCOLOGY 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'. AMER ASSOC IMMUNOLOGISTS 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'. BLACKWELL PUBLISHING 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'. NATURE PUBLISHING GROUP 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 14 (3), pp. 912-923.
  • 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'. BENTHAM SCIENCE PUBL LTD CURRENT PHARMACEUTICAL DESIGN, 14 (22), pp. 2229-2251.
  • 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'. AMER ASSOC CANCER RESEARCH CLINICAL CANCER RESEARCH, 14 (1), pp. 259-269.
  • 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'. AMER ASSOC CANCER RESEARCH 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.'. AMER ASSOC CANCER RESEARCH 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'. BLACKWELL PUBLISHING 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'. AMER ASSOC CANCER RESEARCH 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'. ELSEVIER SCIENCE INC 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'. BLACKWELL PUBLISHING 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'. ELSEVIER ACADEMIC PRESS INC 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'. AMER ASSOC CANCER RESEARCH 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'. PERGAMON-ELSEVIER SCIENCE LTD EJC SUPPLEMENTS, 4 (12), pp. 108-108.
  • 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'. BIOMED CENTRAL LTD MOLECULAR CANCER, 5 Article number ARTN 51
  • 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'. ELSEVIER SCIENCE INC JOURNAL OF UROLOGY, 176 (5), pp. 2255-2261.
  • Chowdhury S, Pandha H. (2006) 'Targeting renal cell carcinoma'. ELSEVIER SCIENCE LONDON 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'. NATURE PUBLISHING GROUP 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'. NATURE PUBLISHING GROUP PROSTATE CANCER AND PROSTATIC DISEASES, 8 (4), pp. 364-368.

Conference papers

  • 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.
  • 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.
  • 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, 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.
  • 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

  • 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.
  • 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.
  • 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.
  • 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.
  • 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, 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, 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.
  • 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.

Books

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

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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