Epstein Barr virus and the development of EBV-specific vaccination
Epstein Barr virus (EBV) is a ubiquitous infectious agent, carried by most adults. It is found in the malignant cells in a number of cancers in humans. These cancers are brought about as a result of complex interactions between host immunity, EBV-driven cell transformation and sometimes the effects of other infectious agents. EBV-positive cancers are uncommon in the UK but represent an important model for understanding human malignancy.
- Cancer Immunity and Immunotherapy Centre – Professor Alan Rickinson, Dr Graham Taylor
- Cancer Research UK Centre for Drug Development – trial sponsor and funder
- A network of seven academic centres contributing to the trials program in the UK including University Hospital Birmingham NHS Foundation Trust (Dr Neil Steven, Dr Andrew Hartley), The Royal Marsden Hospital, Sutton (Professor Kevin Harrington), Aintree University Hospitals NHS Foundation Trust (Professor Terry Jones), University College London Hospitals (Dr Martin Foster), The Beatson West of Scotland Treatment Centre (Dr Mohammed Rizawanullah), Velindre NHS Trust, Cardiff (Dr Mererid Evans)
- The Chinese University of Hong Kong - Dr Edwin Hui and Professor Anthony Chan
Efficacy of recombinant Epstein-Barr virus (EBV) vaccine in patients with nasopharyngeal cancer who had residual EBV DNA load after conventional therapy – Hong Kong, China, CI Prof Chan.
A Cancer Research UK Phase Ib trial to determine the safety, tolerability and immunogenicity of extended schedule vaccination with MVA-EBNA1/LMP2 in patients with Epstein Barr Virus positive nasopharyngeal carcinoma – UK, CI Neil Steven. Accrual completed March 2015.
I am clinical chief investigator for the UK phase IA clinical trial (PMID:25124688) and the subsequent CR-UK-sponsored phase IB trial of MVA vaccination in people with EBV+ cancer. I am also co-investigator on the parallel phase IA trial of the vaccine in Hong Kong (PMID: 23348421) and current phase II trial in Hong Kong looking at the vaccine’s clinical efficacy as monotherapy. In the UK, I have overall responsibility for and active engagement in all aspects of conduct of the trials, from experimental design through clinical operations to data analysis, writing the trial reports and manuscript. I am privileged to lead a network of seven academic centres contributing to the trials program in the UK including University Hospital Birmingham NHS Foundation Trust (Dr Neil Steven, Dr Andrew Hartley), The Royal Marsden Hospital, Sutton (Professor Kevin Harrington), Aintree University Hospitals NHS Foundation Trust (Professor Terry Jones), University College London Hospitals (Dr Martin Foster), The Beatson West of Scotland Treatment Centre (Dr Mohammed Rizawanullah), Velindre NHS Trust, Cardiff (Dr Mererid Evans). Building on data from these trials, I am preparing the funding application for the next phase of development, in partnership with the pharmaceutical industry.
The University of Birmingham has a long history of pioneering research in the virology and immunology of Epstein Barr virus (EBV). My own contribution in this includes analysis of viral behaviour and immune responses in primary infection and immune compromised patients (PMID: 7933121, 8705861, 8920868, 9151898, 9565632, 12869487). Then in 2004 we published the design of a vaccine against EBV+ cancer cells, work led by Dr Graham Taylor and Professor Rickinson (PMID: 14694109). I then developed the clinical trial protocol for phase IA trials of the vaccine in the UK and in Hong Kong, the latter led by Professor Anthony Chan, and secured regulatory approval at a time when gene therapy was relatively novel. These trials were completed demonstrating (i) a dose-response relationship for immunogenicity permitting selection of the dose for further investigation, (ii) that immune responses could be generated on diverse genetic backgrounds and (iii) that vaccination armed immune cells as well as increasing their number (PMID:25124688 and 23348421). These data supported our development of the UK phase IB trial sponsored by CR-UK to further characterise immune responses and seek an early clinical signal of activity. This trial is now complete and analysis underway leading to reporting in 2016. In parallel the vaccine is under phase II investigation in Hong Kong with immune analysis conducted in Birmingham. We expect to report on this in 2017. For this work, we were awarded the CR-UK Cancer Translational Research Prize 2015. We are now planning a further randomised phase II trial of vaccination in combination with immune checkpoint blockade, in partnership with a pharmaceutical company and CR-UK. This will be a definitive and highly influential trial for the field of cancer vaccination: determining in a well characterised system whether vaccination plus checkpoint blockade results in increased clinical responses compared to checkpoint blockade alone.
Merkel cell carcinoma
MCC is a rare skin cancer (age standardised incidence 0.3/100000) of older people, is locally invasive and has high metastatic potential. A paucity of trials means current treatments are diverse and potentially sub-optimal. Merkel cell polyoma virus (MCPyV) in the MCC malignant genome and viral proteins may drive cellular processes affecting invasiveness and metastatic potential.
We track all patients with MCC in the Birmingham skin clinic and routinely obtain consent for use of samples and data for research.
- University Hospital Birmingham NHS Foundation Trust Skin Specialist Multi-disciplinary Team
- Cancer Immunity and Immunotherapy Centre – Dr Andrew Hislop (I co-supervise Dr Lalit Pallan, MRC Clinical Research Fellow, who is completing his doctoral research for a project entitled “Defining T cell immunity to Merkel cell Virus”)
- NIHR Clinical Research Network: West Midlands – Clinical Lead for skin cancer trials
- NCRI Skin Cancer Clinical Studies Group – non melanoma skin cancers sub-group
- University of Leeds, School of Molecular and Cellular Biology – Professor Adrian Whitehouse
- International Rare Cancer Initiative – UK lead for the MCC workstream within the uveal melanoma group of the, led by Professor Jurgen Becker
- Member of MCC Multi-centre Interest Group (http://www.merkelcell.org/) led By Professor Paul Nghiem, Fred Hutchinson Cancer Research centre
UK-MCC1 - Pazopanib in Advanced Merkel Cell Carcinoma. CR UK CTAAC. UK – CI Dr Paul Nathan.
Rational MCC - A randomised trial comparing surgical and radiotherapy strategies enabling rational treatment selection for primary Merkel Cell Carcinoma (MCC), a rare virus and immune-related aggressive skin cancer. MRC EME funder trial 14/150 (12/205 Very Rare Diseases project number 112195): Chief Investigator – multi-centre trial opening 2016
I was the lead investigator on initial investigations demonstrating the stalling of immune cells outside tumour nests and that the few infiltrating tumour nests were functionally inert (PMID 24961933). I am co-investigator for the CR-UK funded trial of pazopanib for people with advanced MCC, responsible for the translational studies. I am the chief investigator for the MRC-funded Rational MCC trial, opening 2016, comparing radiotherapy with surgery as first treatment for primary MCC and with translational studies testing immune parameters in relation to treatment outcomes.
The manuscript “Inflammatory cell distribution in Merkel cell carcinoma” (PMID 24961933) is the result of a pilot study undertaken jointly in the University of Birmingham and University Hospital Birmingham. This study pioneered the use of fluorescent multi-channel immunohistochemistry on archival paraffin embedded tumour tissue, permitting testing multiple parameters on cells confirming their identify and describing their function. This approach is now embedded in new immune profiling approaches to cancer. The study demonstrated the stalling of immune cells outside tumour nests and that the few infiltrating tumour nests were functionally inert. This publication contributed to the design of systematic translational work as part of the newly funded UK-wide Rational MCC Trial, testing immune parameters in relation to treatment outcomes. The Rational MCC trial compares radiotherapy and surgery as first treatment against primary MCC. It will be highly influential, being the first prospective study of management of MCC in the UK as well as being the first randomised trial addressing this question and the only the second randomised trial for this cancer in the world. MCC is rare but represents a fascinating biological model for cancer. Furthermore, this trial will also serve as an exemplar for design of trials for rare diseases.
Immunotherapy against cancer
The management of patients with melanoma is founded on the use of molecularly targeted agents and immune checkpoint inhibitors. Responses against melanoma induced by anti-CTLA4 target diverse tumour antigen classes. Anti-PD1 appears to target pre-activated responses that have homed to the tumour site. I have extensive experience in using anti-CTLA4 (>120 patients treated to date) and anti-PD1 (~30 patients treated to date). I am contributing to ongoing industry-sponsored trials using these agents. We have experience in developing clinical trials of cancer vaccines for melanoma, liver cancer and against virus-positive cancers.
We are auditing outcomes of patients treated with immunotherapy in relation to biological profiling and as a basis for developing guidelines for managing immune related adverse events. We are developing a clinical trial investigating supportive care measures for colitis resulting from immune therapy.
I work with Dr Curbishley in the Liver Biomedical Research Unit to develop a more tractable cellular vehicle for tumour cell vaccination (MRC Confidence in Concept The development of Human γδ-T Antigen Presenting Cells as a clinical grade cancer vaccine) allowing us to dissect the unique pattern of immune reactivities generated in individuals and thus understand mechanistically how vaccination might add to or synergise with immune checkpoint inhibition.
- University Hospital Birmingham NHS Foundation Trust Skin Specialist Multi-disciplinary Team
- Cardiff Institute of Infection & Immunity, Cardiff University – Professor Bernhard Moser
- Liver Biomedical Research Unit, University of Birmingham – Dr Stuart Curbishley
- Cancer Immunity and Immunotherapy Centre – Dr Graham Taylor, Professor Gary Middleton, Professor Ben Willcox
Further information can be found at: http://www.qehb.org/skincancer/