Title: Experimental Cancer Medicine Centre (ECMC): Oxford
Funder: Cancer Research UK

Abstract: Goals and ObjectivesTo apply our basic scientific discoveries in cancer biology to the development of novel cancer therapies. To use these discoveries to develop prognostic and predictive markers, and to individualise patient care. To use novel monitoring techniques to enhance the rate of drug development. To train staff in translational research. Centre expertise - Angiogenesis inhibitor studies and assays - The measurement of circulating endothelial cells and endothelial cell precursors is complex and a recent review showed that in four studies the normal range for CECs is 1 per ml, in another four studies it was approximately 100 per ml, and in one study it was 8,000 per ml. We have developed an assay that is highly reproducible, matches the middle of the range of these assays and has shown a striking correlation of VEGF and SDF1 with the EPC levels, suggesting that our assay is picking up cells of highly functional significance. We have already offered this assay to other centres as part of a collaboration, for example in the joint development of GSAO with Manchester, and in vascular targeting research with Mount Vernon. In addition, new assays for measuring circulating RNA released from endothelial cells have been similarly assessed and will be applied to two studies of vascular targeting and other studies of angiogenesis inhibitors. We are willing to carry out these assays as part of a collaboration using the ECMC resources or host staff with training. As part of a European Union grant we have collaborated with two other centres in Milan and Amsterdam to standardise the assays internationally and also spent time with the NIH team, and our results are highly comparable to theirs. As these types of assays seem to become more important, particularly the EPC and necrotic CECs seem to be excellent surrogate markers in preclinical studies, they need to be applied in clinical trials. DNA Repair Grouping The three research groups and two lead clinicians with a major interest in DNA repair represent one of the largest groupings of its type in the UK with strong translational and clinical links. We have developed, and are able to execute, an extensive range of biochemical and cellular assays covering all major DNA repair pathways and have employed these in both clinical trials and pre-clinical agent development. This expertise is, and will continue to be, utilised in national collaborations with ECMC members, strengthening the DNA damage and repair portfolio of ECMC. Immunology Over the last five years we have developed novel protocols to study the binding of lipid ligands to CD1 molecules and activation of CD1d restricted iNKT cells. The results of these studies have led to the identification of a novel vaccination strategy and a novel family of iNKT cell agonists, which we are keen to take into the clinic within the next two years. The results of structural, kinetic and functional studies, have facilitated the process of rational optimisation of α-GalCer analogues and have led to the identification of a series of novel synthetic compounds capable of binding to CD1d molecules and activating human and mouse iNKT cells, resulting in rapid DC maturation and T cell priming. This work has been made possible by a network of collaboration with organic chemists from the University of Konstanz and Birmingham and structural biologists and support from the Ludwig Institute for cancer Research and Cancer Research UK. NBS The NBS SCI laboratories comprise a network of 9 laboratories in England that not only provide processed and banked haemopoietic stem cells for circa 40% of transplants in England to NHS patients with haematological malignancies, but also provide the laboratory lead in delivering cellular therapies to cancer patients involved in clinical immunotherapy trials at four of the current NTRAC centres. Cellular immunotherapies will be provided via the CGMP grade MHRA and JACIE accredited laboratory in Oxford in partnership, using the nationally established network and standards (e.g. trained staff, quality systems, tracking systems, SOPs, accredited facilities, emergency planning etc) and the NBS SCI laboratories within the NTRAC network in Birmingham, Leeds, and Manchester. The technology for the CGMP production of tetramers currently taking place in Birmingham is an example of the utility of this partnership as is the expertise developed in the various laboratories in the production of dendritic and T cell therapies for cancer patients. Molecular Pathology Group This group makes monoclonal antibodies to targets of interest prior to clinical trials to help develop suitable ways of monitoring therapy. They also collaborate with the teams at the WIMM generating monoclonal antibodies for the new targets that have been described above. In addition, tumour banks, tissue arrays, cDNA array analysis, in situ hybridisation can be carried out to support preclinical and clinical studies. Tissue banks have been developed for bladder and breast cancer, and are being developed for colon and lung cancer. These can be made available to other centres. Clinical focus areas: Radiotherapy, Surgery, Phase 0 trials. Disease focus areas: Breast, Bladder, Cervical, Colorectal, Kidney, Lung, Melanoma, Oesophageal, Pancreatic, Prostate, All types.


Research activity codes: 6.9 RESOURCES AND INFRASTRUCTURE (TREATMENT EVALUATION);4.5 RESOURCES AND INFRASTRUCTURE (DETECTION)
Health categories: CANCER AND NEOPLASMS