Epstein Barr virus and the development of EBV-specific vaccination

Background

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. 

Contribution

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.

Merkel cell carcinoma

Background

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.  

Contribution

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.

Immunotherapy against cancer

Background

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. 

Contribution

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. 

CR UK Clinical Trials Unit

A leading UK trials unit

The CRCTU based within the Institute of Cancer and Genomic Sciences, is one of the largest and most highly regarded trials units for cancer in the UK and has an international profile.  The programme grant for the CRCTU has been renewed in the Quinquennial Reviewin2012 for a total of £10.5 million core funding from CR UK.  The Independent Scientific Review Party awarded the following scores:

Past Work: Forefront/Outstanding

Future - Portfolio of Trials: Forefront/Outstanding

Future – Collaborations: Outstanding

Future – Operating Standards: Forefront/Outstanding

Future Work (overall): Forefront/Outstanding

In addition to CR UK core funding, the CRCTU brings in additional project funding and non-CRUK core funding (the 5 year research income between 2007-2012 in over £17M). The CRCTU currently employs 137 members of staff and runs a portfolio of over 130 clinical trials in a wide range of cancers.

Current responsibilities

I am a co-grant holder of the CRCTU (headed by Director, Professor Pamela Kearns).  I have a senior academic leadership role within the CRCTU as Deputy Clinical Director and Clinical Lead for early phase trials in adult solid cancer. In 2011, I supported Professor Morton to defend the CR UK/NIHR grant for the Experimental Cancer Medicine Centre (ECMC) for the University and UHBFT.  I am ECMC lead for novel therapies and the ECMC contributes funding to the CRCTU and to UBHFT for this theme.  I support the development of early phase trial grant applications for other investigators, including the HepaVAC programme in the BRU and piloting the early steps of CR-UK’s flagship Stratified Medicine Programme II Lung Matrix Trial within the CRCTU in 2013.

The team

My workis focussed on the Early Drug Development (EDD) team of eleven whole time equivalent (WTE) staff including 2 WTE research nurses, managed by a recently appointed team leader, Dr Crack.

We retain a complement of three part-time research nurses with specialised skills within the EDD team, who work closely with the WTCRF and UHBFT research and development team. 

I work closely with the biostatistics team (Professor Cindy Billingham, Dr Christina Yap) and with rapidly developing expertise in the methodology of early phase trials, including its application to immunotherapy.

Our purpose

Our purpose is to create a portfolio of internationally competitive early phase trials and trials of novel therapies.  The scope of work includes (i) specialist areas associated with local expertise such as viral-associated cancer, cancer immunology, gene therapy, stratified medicine, cancer epigenetics, angiogenesis, DNA damage and repair (ii) all solid cancers, including hepatic cancer and (iii) both  treatment and prevention of cancer

A changing role over a decade

I have had a leadership role in the CRCTU since 2004.  My role within the CRCTU and the University has evolved over a decade in response to new challenges.  I have been a major contributing investigator to the site visits of the CRCTU from 2005 to 2012.  I have led the CRCTU and University team in managing two audits by the statutory body the MHRA.