A key strength of the Cancer Sciences Group is the interdisciplinary nature of the work that is undertaken ranging from basic cellular and molecular biology right through to the epidemiology of service provision. Major strengths include basic and translational immunology and tumour survival in lymphoma and solid tumours.
The Cancer Sciences Research Group incorporates the Southampton Cancer Research UK Centre. Research here is characterised by highly productive collaborations between laboratory-based cancer researchers, clinicians who specialise in treating cancer patients, and research teams with expertise in, for example, Medicinal Chemistry or Biophysical Sciences.
1. Immunotherapeutic Antibodies and Vaccines.
We have made significant contributions to the development of new cancer immunotherapy treatments by building on a deep understanding of antibody effector functions, particularly mediated via Fc receptors, and the immunobiology of cytotoxic T cells. In addition, the group continues to refine DNA cancer vaccines for targeted therapy, and has completed 5 PhaseI/II trials in lymphoma, multiple myeloma and solid cancers since 2008. We continue to develop GCLP level human immunometry and have extended our capability to full cell-mediated immune profiling at the functional level and exome-based NGS thanks to the CRUK/DH funded Experimental Centre for Cancer Medicine and our new 400m2 GCLP laboratory in the SCBR.
2. Molecular and Cellular Immunology
The development of new T cell based immunotherapies in cancer is supported by a deep understanding of the mechanisms of antigen processing and presentation, co-stimulation and the role of the tumour microenvironment in shaping tumour growth. We are investigating the molecular mechanism of peptide antigen selection in antigen presentation, and how polymorphic variation in the enzymes that generate antigenic peptides influences immune responsiveness.
3. Tumour Immunological Environment
We are investigating the function of the myofibroblast-rich stroma of head and neck and lung cancers in supressing anti-tumour T cell responses in cancer patients. This work focusses on improving immunotherapy in the context of stromal immunosuppression, and has led to a new programme aimed at predicting cancer patients’ responsiveness to immunotherapy and vaccination based on genomic and epigenomic profiling of tumour, stroma, and infiltrating immunocytes at single-cell resolution.
4. Leukaemia and Lymphoma Research Centre of Excellence for Research on Chronic Lymphocytic Leukaemia (CLL).
This work exploits strong collaboration with the Wessex Regional Genetics Laboratories, the Haematology Departments at Southampton General Hospital, the Royal Bournemouth Hospital, and the Institute for Life Sciences; and integrates with the UK national CLL strategy, via the UK CLL Trials Biobank.
5. Translational and Clinical Research
The Central South Coast Cancer Research Network (CSCCRN) is one of the largest and most active in the country; 1200 patients enter cancer trials in Southampton annually. It is supported by the DH/CRUK Clinical Trials Unit and focuses on early phase and multi-centre clinical research in oncology and surgery, predominantly in immunotherapy and lymphoid biology. Cancer Stratification remains a high priority in the group and over the last 5 years for example we have identified clinical subgroups and recruited 2000 subjects to national and international collaborative studies facilitating the discovery of breast, colorectal and other cancer predisposition genes, and the characterisation of associated tumour phenotypes.
We have elucidated the effector mechanism of the FDA-approved anti-CD20 therapeutic mAb, ofatumumab and experimental therapeutic obinutuzumab and demonstrated that FcgRIIb expression on tumour targets is a strong negative prognostic factor for anti-CD20 treatment.
Our research linking the IGHV mutational status to B-cell receptor signalling in lymphoid malignancies has led to identification of follicular B cell lymphoma endotypes allowing stratified approaches to therapy.
We have identified of somatic alterations driving CLL, and novel methods for inducing selective apoptosis in CLL cells.
We have discovered a new CtBP regulatory mechanism linked to metabolic status in breast cancer and the chemical synthesis of a novel class of inhibitors that target CtBP dimerization.
In one of the largest clinical UK studies of its kind, we found that the strongest independent risk factor for early patient death in oral cancer patients was a myofibroblast-rich stroma, allowing early identification of aggressive cancers and the specific mechanism through which cancer cells generate a stromal response capable of supressing adaptive immunity.
We were the first to demonstrate functional polymorphism in the antigen processing enzyme ERAP1 thus providing a mechanistic rationale for its association with diseases such as ankylosing spondylitis, psoriasis and cervical cancer.
The Cancer Sciences Group has taken 12 reagents (DNA vaccines; monoclonal antibodies; radioimmunoconjugates) from our own laboratories into clinical trials, with support from pharma, biotech, research council and charity funding.
We were one of the first to identify immunostimulatory mAb and we have gone on to deliver a first-in-man anti-CD40 mAb, ChiLob-7-4, now entering phase II trials. With CR UK, we have also established an ‘Antibody Discovery’ programme to generate a pipeline of immunostimulatory reagents which target the immune co-receptors of the TNFR superfamily. The first, an anti-CD27, has been developed in partnership with Celldex therapeutics, and is now in phase I trials. Our work on the mechanism of anti-CD20 immunotherapy has led to a new collaborative initiative with the Swedish Biotech company, BioInvent.
We were the first to define the immunological functions for the MHC I cofactors calreticulin and tapasin and the first to relate these to the generation of immunodominance to experimental vaccines. In collaboration with Microsoft UK, we have developed a new computational model that will help predict the immunological outcome of various immunotherapeutic approaches.