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Dr Guy Simpson


Research Fellow Oncology
BSc PhD,
+44 (0)1483 688600
30 PGM 02
9am to 5pm Mon-Fri

Academic and research departments

School of Biosciences and Medicine.

Biography

2004 PhD        Optimising therapeutic herpes simplex vectors for cancer.

                        BioVex Ltd/UCL The Windeyer Institute, 46 Cleveland Street, London.

1997 MPhil     Human endogenous retroviral particles expressed in the placenta.

                        Institute of Cancer Research, Chester Beatty Labs, Fulham Road, London.

1988 B.Sc.      Honours Degree in Bioanalytical Science (Class IIi).

                        Kingston Polytechnic, Surrey.

2004-2007       Senior Scientist, UCL (Biovex Ltd), The Windeyer Institute, London..

1999-2004       Scientist UCL (Biovex Ltd), The Windeyer Institute, London.

1995-1999       Research Associate, Prof Thomas F. Schulz, University of Liverpool.

1989-1995      Scientific Officer, Prof Robin Weiss, Institute of Cancer Research

Research Interests

Viral Vectors

Molecular Biology

Tumour Biology

Gene Therapy

My publications

Publications

L Heinemann, GR Simpson, NE Annels, R Vile, A Melcher, R Prestwich, KJ Harrington, HS Pandha (2010)The Effect of Cell Cycle Synchronization on Tumor Sensitivity to Reovirus Oncolysis, In: MOLECULAR THERAPY18(12)pp. 2085-2093 NATURE PUBLISHING GROUP
GR Simpson, M Ajaz, FA Launchbury, G Bolton, AA Melcher, KJ Harrington, GG Au, DR Shafren, HS Pandha (2014)Major synergy between Coxsackievirus A21 (CAVATAK (TM)) and radiotherapy or chemotherapy in bladder cancer, In: HUMAN GENE THERAPY25(12)pp. A13-A13
GC Bolton, GR Simpson, M Coffey, K Harrington, R Morgan, N Annels, FA Launchbury, M Ajaz, H Pandha (2014)Resistance to Oncolytic Reovirus is associated with high expression of Yes-Associated Protein-1 (YAP-1) in Head and Neck Cancer, In: HUMAN GENE THERAPY25(12)pp. A12-A13
C Comins, Guy Simpson, William Rogers, Kate Relph, K Harrington, A Melcher, V Roulestone, J Kyula, Hardev Pandha (2018)Synergistic anti-tumour effects of rapamycin and oncolytic reovirus, In: Cancer Gene Therapy25pp. 148-160 Nature Publishing Group

There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent,Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anti-cancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an anti-reovirus neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin, However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic anti-tumour efficacy of reovirus and rapamycin combination.

NE Annels, GR Simpson, S Bokaee, C Riley, M Denyer, H Pandha, R Morgan (2012)Modulation of Regulatory T Cells by Targeting The NFAT-FOXP3 Protein: Protein Interaction, In: JOURNAL OF IMMUNOTHERAPY35(9)pp. 775-775
NE Annels, C Riley, S Bokaee, M Denyer, GR Simpson, H Pandha (2010)EN2: A Novel Immunotherapeutic Target for Melanoma, In: J IMMUNOTHER33(8)pp. 891-891
L Heinemann, G Simpson, K Harrington, A Melcher, MC Coffey, HS Pandha (2008)Synergistic anti-tumour activity of oncolytic Reovirus and cisplatin in a B16.F10 mouse melanoma model, In: EJC SUPPLEMENTS6(12)pp. 99-99
KL Relph, H Pandha, GR Simpson, A Melcher, K Harrington (2016)Cancer immunotherapy via combining oncolytic virotherapy with chemotherapy: recent advances, In: Oncolytic Virotherapy2016(5)pp. 1-13 Dove Medical Press

Oncolytic viruses are multifunctional anticancer agents with huge clinical potential, and have recently passed the randomized Phase III clinical trial hurdle. Both wild-type and engineered viruses have been selected for targeting of specific cancers, to elicit cytotoxicity, and also to generate antitumor immunity. Single-agent oncolytic virotherapy treatments have resulted in modest effects in the clinic. There is increasing interest in their combination with cytotoxic agents, radiotherapy and immune-checkpoint inhibitors. Similarly to oncolytic viruses, the benefits of chemotherapeutic agents may be that they induce systemic antitumor immunity through the induction of immunogenic cell death of cancer cells. Combining these two treatment modalities has to date resulted in significant potential in vitro and in vivo synergies through various mechanisms without any apparent additional toxicities. Chemotherapy has been and will continue to be integral to the management of advanced cancers. This review therefore focuses on the potential for a number of common cytotoxic agents to be combined with clinically relevant oncolytic viruses. In many cases, this combined approach has already advanced to the clinical trial arena.

R Morgan, G Simpson, S Gray, C Gillett, Z Tabi, J Spicer, KJ Harrington, HS Pandha (2016)HOX transcription factors are potential targets and markers in malignant mesothelioma, In: BMC CANCER16ARTN 85 BIOMED CENTRAL LTD
DL Price, S-F Lin, Z Han, G Simpson, RS Coffin, J Wong, S Li, Y Fong, RJ Wong (2010)Oncolysis Using Herpes Simplex Virus Type 1 Engineered to Express Cytosine Deaminase and a Fusogenic Glycoprotein for Head and Neck Squamous Cell Carcinoma, In: ARCHIVES OF OTOLARYNGOLOGY-HEAD & NECK SURGERY136(2)pp. 151-158 AMER MEDICAL ASSOC
RS Coffin, B Liu, Z Han, M Assenberg, S Thomas, J Hu, G Simpson (2006)OncoVEX: A Family of Oncolytic Herpes Simplex Viruses Optimised for Therapeutic Use, In: MOLECULAR THERAPY13pp. S64-S64 NATURE PUBLISHING GROUP
L Heinemann, GR Simpson, A Boxall, T Kottke, KL Relph, R Vile, A Melcher, R Prestwich, KJ Harrington, R Morgan, HS Pandha (2011)Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer., In: BMC Cancer11pp. 221-? Biomed Central

Reovirus type 3 Dearing (T3D) has demonstrated oncolytic activity in vitro, in in vivo murine models and in early clinical trials. However the true potential of oncolytic viruses may only be realized fully in combination with other modalities such as chemotherapy, targeted therapy and radiotherapy. In this study, we examine the oncolytic activity of reovirus T3D and chemotherapeutic agents against human prostate cancer cell lines, with particular focus on the highly metastatic cell line PC3 and the chemotherapeutic agent docetaxel. Docetaxel is the standard of care for metastatic prostate cancer and acts by disrupting the normal process of microtubule assembly and disassembly. Reoviruses have been shown to associate with microtubules and may require this association for efficient viral replication.

Nicola Annels, Mehreen Arif, Guy Simpson, Mick Denyer, Carla Moller-Levet, David Mansfield, Rachel Butler, Darren Shafren, Gough Au, Margaret Knowles, Kevin Harrington, Richard Vile, Alan Melcher, Hardev Pandha (2018)Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus, In: Molecular Therapy - Oncolytics9pp. 1-12 Elsevier

As a clinical setting in which local live biological therapy is already well established, non-muscle invasive bladder cancer (NMIBC) presents intriguing opportunities for oncolytic virotherapy. Coxsackievirus A21 (CVA21) is a novel intercellular adhesion molecule-1 (ICAM-1)-targeted immunotherapeutic virus. This study investigated CVA21-induced cytotoxicity in a panel of human bladder cancer cell lines, revealing a range of sensitivities largely correlating with expression of the viral receptor ICAM-1. CVA21 in combination with low doses of mitomycin-C enhanced CVA21 viral replication and oncolysis by increasing surface expression levels of ICAM-1. This was further confirmed using 300-μm precision slices of NMIBC where levels of virus protein expression and induction of apoptosis were enhanced with prior exposure to mitomycin-C. Given the importance of the immunogenicity of dying cancer cells for triggering tumor-specific responses and long-term therapeutic success, the ability of CVA21 to induce immunogenic cell death was investigated. CVA21 induced immunogenic apoptosis in bladder cancer cell lines, as evidenced by expression of the immunogenic cell death (ICD) determinant calreticulin, and HMGB-1 release and the ability to reject MB49 tumors in syngeneic mice after vaccination with MB49 cells undergoing CVA21 induced ICD. Such CVA21 immunotherapy could offer a potentially less toxic, more effective option for the treatment of bladder cancer.

R Morgan, A Boxall, KJ Harrington, GR Simpson, A Michael, HS Pandha (2014)Targeting HOX transcription factors in prostate cancer, In: BMC UROLOGY14ARTN 1pp. ?-? BIOMED CENTRAL LTD
Richard Morgan, A Boxall, Guy Simpson, Agnieszka Michael, Hardev Pandha, KJ Harrington, C Gillett (2012)Targeting the HOX/PBX dimer in breast cancer, In: Breast Cancer Research and Treatment136(2)pp. 389-398 Springer Verlag

The HOX genes are a family of closely related transcription factors that help to define the identity of cells and tissues during embryonic development and which are also frequently deregulated in a number of malignancies, including breast cancer. While relatively little is known about the roles that individual HOX genes play in cancer, it is however clear that these roles can be both contradictory, with some members acting as oncogenes and some as tumor suppressors, and also redundant, with several genes essentially having the same function. Here, we have attempted to address this complexity using the HXR9 peptide to target the interaction between HOX proteins and PBX, a second transcription factor that serves as a common co-factor for many HOX proteins. We show that HXR9 causes apoptosis in a number of breast cancer-derived cell lines and that sensitivity to HXR9 is directly related to the averaged expression of HOX genes HOXB1 through to HOXB9, providing a potential biomarker to predict the sensitivity of breast tumors to HXR9 or its derivatives. Measuring the expression of HOX genes HOXB1-HOXB9 in primary tumors revealed that a subset of tumors show highly elevated expression indicating that these might be potentially very sensitive to killing by HXR9. Furthermore, we show that while HXR9 blocks the oncogenic activity of HOX genes, it does not affect the known tumor-suppressor properties of a subset of HOX genes in breast cancer.

GR Simpson, A Horvath, NE Annels, T Pencavel, S Metcalf, R Seth, P Peschard, T Price, RS Coffin, H Mostafid, AA Melcher, KJ Harrington, HS Pandha (2012)Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer, In: BRITISH JOURNAL OF CANCER106(3)pp. 496-507
R Morgan, A Boxall, KJ Harrington, GR Simpson, C Gillett, A Michael, HS Pandha (2012)Targeting the HOX/PBX dimer in breast cancer., In: Breast Cancer Res Treat136(2)pp. 389-398 Springer

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.

S Gogalic, U Sauer, S Doppler, A Heinzel, P Perco, A Lukas, Guy Simpson, Hardev Pandha, A Horvath, C Preininger (2017)Validation of a protein panel for the non-invasive detection of recurrent non-muscle invasive bladder cancer, In: Biomarkers22(7)pp. 674-681 Taylor & Francis

Context: About 50–70% of patients with non-muscle invasive bladder cancer (NMIBC) experience relapse of disease. Objective: To establish a panel of protein biomarkers incorporated in a multiplexed microarray (BCa chip) and a classifier for diagnosing recurrent NMIBC. Materials and methods: Urine samples from 45 patients were tested. Diagnostic performance was evaluated by receiver operating characteristic (ROC) analysis. Results: A multi biomarker panel (ECadh, IL8, MMP9, EN2, VEGF, past recurrences, BCG therapies and stage at diagnosis) was identified yielding an area under the curve of 0.96. Discussion and conclusion: This biomarker panel represents a potential diagnostic tool for noninvasive diagnosis of recurrent NMIBC.

R Seth, AA Khan, TD Pencavel, MJ Wilkinson, JN Kyula, G Simpson, H Pandha, A Melcher, R Vile, PA Harris, KJ Harrington (2015)Adenovirally Delivered Enzyme Prodrug Therapy with Herpes Simplex Virus-Thymidine Kinase in Composite Tissue Free Flaps Shows Therapeutic Efficacy in Rat Models of Glioma, In: PLASTIC AND RECONSTRUCTIVE SURGERY135(2)pp. 475-487 LIPPINCOTT WILLIAMS & WILKINS

A large number of oncolytic viral vectors are currently under clinical development for cancer therapy. Herpes simplex virus type 1 (HSV-1) has demonstrated particular promise in this field, showing genetically engineered selective tumor replication and cytotoxicity in a wide variety of tumor types, without damaging healthy tissues. Enhanced activity has been observed when a range of therapeutic genes has been inserted into various oncolytic HSV genomes. Here, we discuss methods used to develop and characterize an oncolytic HSV virus that combines expression of a highly potent prodrug activating gene (yeast cytosine deaminase/uracil phosphoribosyltransferase fusion [Fcy::Fur]) and the fusogenic glycoprotein from gibbon ape leukemia virus (GALV) for enhanced local tumor control.

Hardev Pandha, Lucy Heinemann, Guy Simpson, A Melcher, R Prestwich, F Errington, M Coffey, KJ Harrington, Richard Morgan (2009)Synergistic Effects of Oncolytic Reovirus and Cisplatin Chemotherapy in Murine Malignant Melanoma, In: Clinical Cancer Research15(19)pp. 6158-6166 American Association for Cancer Research
S Pandha, GR Simpson, A Horvath, RS Coffin, T Pencavel, K Harrington (2011)Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer (visualised by micro CT), In: BRITISH JOURNAL OF SURGERY98pp. 52-53
Nicola E Annels, David Mansfield, Mehreen Arif, Carmen Ballesteros-Merino, Guy R Simpson, Mick Denyer, Sarbjinder S Sandhu, Alan Melcher, Kevin J Harrington, BronwYn Davies, Gough Au, Mark Grose, Izhar N Bagwan, Bernard A. Fox, Richard G Vile, Hugh Mostafid, Darren Shafren, Hardev Pandha (2019)Viral targeting of non-muscle invasive bladder cancer and priming of anti-tumour immunity following intravesical Coxsackievirus A21, In: Clinical Cancer Research American Association for Cancer Research

Purpose: The CANON (CAVATAK in NON-muscle invasive bladder cancer) study evaluated a novel ICAM-1-targeted immunotherapeutic-coxsackievirus A21 as a novel oncolytic agent against bladder cancer. Experimental Design: Fifteen patients enrolled on this 'window of opportunity' phase 1 study, exposing primary bladder cancers to CAVATAK prior to surgery. The first nine patients received intravesical administration of monotherapy CAVATAK; in the second stage, six patients received CAVATAK with a sub-therapeutic dose of mitomycinC, known to enhance expression of ICAM-1 on bladder cancer cells. The primary endpoint was to determine patient safety and maximum tolerated dose. Secondary endpoints were evidence of viral replication, induction of inflammatory cytokines, anti-tumour activity and viral-induced changes in resected tissue. Results: Clinical activity of CAVATAK was demonstrated by induction of tumour inflammation and haemorrhage following either single or multiple administrations of CAVATAK in multiple patients, and a complete resolution of tumour in one patient. Whether used alone or in combination with mitomycinC, CAVATAK caused marked inflammatory changes within NMIBC tissue biopsies by up-regulating interferon-inducible genes including both immune checkpoint-inhibitory genes (PD-L1 and LAG3) and Th1-associated chemokines as well as induction of the innate activator RIG-I, compared to bladder cancer tissue from untreated patients. No significant toxicities were reported in any patient, from either virus or combination therapy. Conclusions: The acceptable safety profile of CAVATAK, proof of viral targeting, replication and tumour cell death together with the virus-mediated increases in "immunological heat" within the tumour microenvironment all indicate that CAVATAK may be potentially considered as a novel therapeutic for NMIBC.

S Pandha, L Heinemann, GR Simpson, A Boxall, K Relph, R Morgan (2011)Synergistic effects of oncolytic reovirus and docetaxel chemotherapy in prostate cancer, In: BRITISH JOURNAL OF SURGERY98pp. 47-48
J Wong, K Kelly, A Mittra, SJ Gonzalez, KY Song, G Simpson, R Coffin, Y Fong (2010)A Third-Generation Herpesvirus Is Effective Against Gastroesophageal Cancer, In: JOURNAL OF SURGICAL RESEARCH163(2)pp. 214-220 ACADEMIC PRESS INC ELSEVIER SCIENCE
GR Simpson, Z Han, B Liu, Y Wang, G Campbell, RS Coffin (2006)Combination of a fusogenic glycoprotein, prodrug activation, and oncolytic herpes simplex virus for enhanced local tumor control, In: CANCER RESEARCH66(9)pp. 4835-4842 AMER ASSOC CANCER RESEARCH
C Comins, GR Simpson, K Relph, KJ Harrington, A Melcher, H Pandha (2013)Reoviral Therapy for Cancer: Strategies for Improving Antitumor Efficacy Using Radio- and Chemotherapypp. 185-198

Reovirus type 3 Dearing (Reolysin, Oncolytics Biotech) is a wild-type double-stranded RNA virus that is ubiquitous and nonpathogenic in humans. It has been shown to be oncolytic by its ability to replicate in transformed cells but not in normal cells. Reovirus has been shown to exert significant antitumor effects in both preclinical in vitro and in vivo studies. In addition, reovirus can activate both innate and adaptive antitumor response against human and murine tumors. However, despite antitumor activity, the responses to reovirus monotherapy in human trials have been modest and short-lived. As a result, a number of potential strategies for improving antitumor efficacy are currently being evaluated. This chapter describes the application of oncolytic reovirus as an anticancer agent, alone or in combination with conventional therapies such as radiotherapy and chemotherapeutics. It also summarizes current clinical trials on reovirus therapy. © 2014 Elsevier Inc. All rights reserved.

M De Paoli, S Gogalic, U Sauer, C Preininger, HS Pandha, G Simpson, A Horvath, C Marquette (2016)Multi-platform biomarker discovery for bladder cancer recurrence diagnosis, In: Disease Markers4591910 Hindawi Publishing Corporation

Purpose. Nonmuscle invasive bladder cancer (BCa) has a high recurrence rate requiring lifelong surveillance. Urinary biomarkers are promising as simple alternatives to cystoscopy for the diagnosis of recurrent bladder cancer. However, no single marker can achieve the required accuracy. The purpose of this study was to select a multiparameter panel, comprising urinary biomarkers and clinical parameters, for BCa recurrence diagnosis. Experimental Design. Candidate biomarkers were measured in urine samples of BCa patients with recurrence and BCa patients without recurrence. A multiplatform strategy was used for marker quantification comprising a multiplexed microarray and an automated platform for ELISA analysis. A multivariate statistical analysis combined the results from both platforms with the collected clinical data. Results. The best performing combination of biomarkers and clinical parameters achieved an AUC value of 0.91, showing better performance than individual parameters. This panel comprises six biomarkers (cadherin-1, IL-8, ErbB2, IL-6, EN2, and VEGF-A) and three clinical parameters (number of past recurrences, number of BCG therapies, and stage at time of diagnosis). Conclusions. The multiparameter panel could be a useful noninvasive tool for BCa surveillance and potentially impact the clinical management of this disease. Validation of results in an independent cohort is warranted.

ZQ Han, M Assenberg, BL Liu, YB Wang, G Simpson, S Thomas, RS Coffin (2007)Development of a second-generation oncolytic Herpes simplex virus expressing TNF alpha for cancer therapy, In: JOURNAL OF GENE MEDICINE9(2)pp. 99-106 JOHN WILEY & SONS LTD
NE Annels, GR Simpson, M Denyer, SE McGrath, G Falgari, E Killick, R Eeles, J Stebbing, D Pchejetski, R Cutress, N Murray, A Michael, H Pandha (2014)Spontaneous antibodies against Engrailed-2 (EN2) protein in patients with prostate cancer, In: CLINICAL AND EXPERIMENTAL IMMUNOLOGY177(2)pp. 428-438 WILEY-BLACKWELL