Viruses to Cure Cancer
Optimal cancer therapy leading to a cure has not been achieved in all tumour types. The best strategies for new treatment remain to be defined, but we need to look beyond traditional chemotherapy and radiotherapy.
Our laboratory has an interest in so called “oncolytic viruses” or cancer killing viruses. The idea behind the concept of oncolytic viruses is best illustrated by the case of an 8 year old boy with Burkitt’s Lymphoma (solid tumour). He became infected with measles virus, after which the tumour went away. This case shows us that oncolytic viruses are able to grow in and kill tumours. More recently it has been shown that the way in which the virus kills the tumour cells is also important. The virus kills the tumour cell in such a way that it kick starts the immune system into mounting an immune response against the tumour. Thus oncolytic viruses have a two pronged approach to cancer killing both directly via infection and lysis and indirectly using the body’s own immune system.
I have worked with oncolytic viruses for many years. In the past I helped to develop a herpes simplex virus that has now gone through all three phases of clinical trials becoming, this year, the first so called “ oncolytic virus “ or cancer killing viruses to show efficacy in patients. Both herpes simplex virus (HSV) and reovirus are able to replicate within tumour cells and not in normal healthy cells of the body due to a specific mutation of a gene common to many cancers. As the virus replicates within the tumour cells new viral offspring are produced. These burst out of the cell causing the tumour cell to pop and die.
Recently I have worked on a cold related virus called Coxsackie virus which is currently in phase I-II clinical trials for melanoma (skin cancer). We have studied the virus in bladder cancer and shown that:
Coxsackie virus can grow in and kill bladder cancer cells.
Combination of Coxsackie virus with either chemotherapy or radiotherapy shows enhanced tumour killing compared to either anti-cancer agent alone.
My work has shown that chemotherapy or radiotherapy improves the ability of the virus to enter tumours cells through entry molecules.
Further work has shown that cancer cells infected with Coxsackie virus express molecules called Immune Death Markers that suggest that this treatment will produce a strong anti-cancer vaccine response.
Results of Our Studies
We have recently published these results: ‘Oncolytic Immunotherapy for Bladder Cancer Using Coxsackie A21 Virus’. Nicola E. Annels, Mehreen Arif, Guy R. Simpson, Mick Denyer, Carla Moller-Levet, David Mansfield Rachel Butler, Darren Shafren, Gough Au, Margaret Knowles, Kevin Harrington, Richard Vile, Alan Melcher, Hardev Pandha.Molecular Therapy Oncolytics. Volume 9, p1–12, 29 June 2018
The preliminary work from these in vitro laboratory studies has allowed us to conduct a phase I first in man clinical trial using the Coxsackie virus in non-muscle invasive bladder cancer. The results of the trial were positive and showed an acceptable safety profile for the Coxsackie Virus (CAVATAK) (no grade 2 or higher adverse events), proof of concept of viral targeting, replication and tumour cell death together with virus-mediated increases in immune response within the tumour microenvironment. This indicates that this oncolytic agent is likely to signal a strong local and systemic anti-tumour immune response. We are soon to publish this data in a high impact journal ‘Phase I/II CANON study: Oncolytic immunotherapy for Non-Muscle Invasive Bladder Cancer (NMIBC) using Intravesical Coxsackievirus A21’. N. E. Annels1, D. Mansfield2, M. Arif1, C. Ballesteros-Merino3, G. Simpson1, S.S. Sandhu4, A. A. Melcher2, K.J. Harrington2, B. Davies4, G. Au4, M. Grose4, I.Bagwan1, B.A. Fox3, Richard Vile5, H. Mostafid1, D. Shafren4, H.S. Pandha1*.
The Prostate Project funded a PhD student Mehreen Arif for 3 years. Mehreen contributed significantly to the coxsackie virus work and has recently submitted her thesis. She is now working at Glaxo Smithkline as a postdoctoral fellow.