Group Leader:
Peter Stern
I am head of the Cancer Research UK Immunology Group at the Paterson Institute for Cancer Research, within The University of Manchester based at the Christie Hospital. I obtained my PhD at University College, London and previously held research positions as: a staff scientist at the MRC Molecular Biology Laboratory, Cambridge; an EMBO Fellow at University of Uppsala, Sweden; a Cancer Research Campaign Fellow and Junior Research Fellow, Linacre College at University of Oxford; as Lecturer at the Medical School, University of Liverpool and as a visiting Professor at Free University of Amsterdam. My work aims to translate knowledge of human papillomavirus driven carcinogenesis or the expression and function of oncofoetal molecules (e.g. 5T4 oncotrophoblast antigen) into new cancer therapies.
Postdoctoral Fellows
Fernanda Castro
Owen McGinn
Tom Southgate
Scientific Officers
Kate Mulryan
Clinical Research Fellows
Sai Daayana
Christy Ralph
Research Students
Mariam Al-Muftah (with Medical Oncology)
Georgi Marinov
Andrzej Rutkowski (with Applied Computational Biology and Bioinformatics Group)
Immunology Group - 5T4 Vaccines
We have established that the 5T4 antigen is expressed by many different carcinomas but is detected at only low levels in some normal epithelia. Tumour expression of 5T4 antigen in colorectal, gastric and ovarian cancer can have prognostic significance. We are investigating the expression of the oncofetal antigen in various human malignancies as well as its potential as a tumour target for immunotherapy. The restricted adult tissue but high frequency and cell surface expression by multiple carcinoma types makes 5T4 antigen an attractive target for both antibody and cell mediated immunotherapies. 5T4 Vaccines: We have shown that attenuated recombinant vaccinia viruses (MVA) encoding human or mouse 5T4 oncofoetal antigen can induce protective immunity to challenge with human or m5T4 expressing tumour models respectively. MORE We have also shown a significant therapeutic effect in the h5T4 models. Furthermore, mice vaccinated with MVA-m5T4 showed no signs of autoimmune toxicity. These data have supported the use of MVA-5T4 for tumor immunotherapy (Mulryan et al 2002).
To study the mechanism of cellular immunity involved in MVA-5T4 vaccine induced protection to tumour challenge in mice, we have generated dendritic cell (DC) lines expressing 5T4 to restimulate lymphocytes in vitro for assay by proliferation or cytotoxicity. We have shown that different gene delivery vectors (MVA, defective adenovirus (Ad) and DCs) can generate specific T cell responses to h5T4. However, detection of T cell activity is greatly influenced by the route, dose, vector and timing of analysis. For example, strong proliferative T cell responses are favoured when vaccinating with MVA-h5T4 intravenously but not CTL activity whereas with Ad-h5T4 given intramuscularly/subcutaneously generates good CTL activity with weak proliferative activity. Antibody responses following homologous vector prime-boost vaccinations are very similar irrespective of dose and, route of virus but are lower if DCs are used. Further preclinical studies of homologous and heterologous vaccine combinations using human 5T4 expressing replication defective adenoviral vectors and retrovirally transduced dendritic cell (DC) lines for induction of tumour protection and therapy of human 5T4 expressing B16 melanoma cells have been completed. Importantly, depletion of CD25 T regulatory cells following tumour challenge, but prior to immunisation, improves the vaccine efficacy offering useful strategies for optimizing 5T4 vaccine immunotherapies ( Ali et al 2006).
Active immunotherapy of CT26 colorectal tumour cells expresing h5T4 antigen. Pulmonary 'metastases' established for 3 days and treatment by vaccination at days 3 and 10. Average number o f metastases obtained using 7 mice per group at day 14 is shown (Mulryan et al. 2002).
Our preclinical studies underwrote the first Oxford BioMedica sponsored clinical trial of Trovax in late stage colorectal patients at the Christie Hospital and this established the safety and immunogenicity of the vaccine (lymphocyte proliferation, ELISPOT and serological assays). Following this, a CR UK sponsored trial in collaboration with Immunology, Medical Oncology and is evaluating the 5T4-MVA vaccine in patients undergoing surgical resection of colorectal liver metastases. The aim is to characterise and quantify the immune response to 5T4 locally in tumour, and in peripheral blood, modified by vaccination before ( and after) resection of the metastases
Recently, we have shown that human CD8-T cell repertoire versus 5T4 antigen exists and can be detected in the absence of CD4 T cells (either helper or regulatory) and HLA-A2 epitopes have been identified (Smyth et al 2006). Significant 5T4 responses of CD4 T cell enriched populations are most apparent with depletion of the CD25 + T cells (Elkord et al unpublished ). These observations imply that the availability of the 5T4 repertoire of both CD4 and CD8 T cells may be optimally accessed in the absence of T regulatory activity. In renal cell carcinoma (RCC) patients there are significantly increased numbers of CD4+CD25high regulatory cells which express the FOXP3 marker (Griffiths et al submitted). These results have prompted a clinical trial aimed at evaluating the safety, immune and clinical consequences of a T regulatory cell depletion protocol in patients with RCC.