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European Network for the identification and validation of Antigens and biomarkers in Cancer and their application in clinical Tumour immunology

Final Report Summary - ENACT (European Network for the identification and validation of Antigens and biomarkers in Cancer and their application in clinical Tumour immunology)

Cancer remains a major health problem, with untold physical, psychological and economic costs to society. Elimination of cancer would reduce health-care costs and enhance the quality of life. Along with cardiovascular disease and ageing, it is currently the most intractable source of suffering and health-care cost. Recent results from immunotherapy trials suggest that inducing tumour-specific T cell responses to tumour antigens can, in some patients, cause regression of tumours or the stabilisation of the disease. However the mechanisms underlying the failure of immunotherapy to control and destroy residual cancer remain to be fully established.

ENACT aimed to identify markers of response and tumour antigens that associate with breast, ovarian, prostate and melanoma cancers, their progression and resistance to immunotherapy. The different types of cancers included in this study addressed the issue of gender-related biomarkers associating with resistance to therapy. Cell biological, immunological, biochemical and molecular biology-based technology were used and the results arising from the study will not only contribute to the development of "next generation" vaccines but will also provide a better understanding of basic biological mechanisms underlying antigen presentation and recognition of tumours by T lymphocytes and natural killer (NK) cells and identify tumour biomarkers associating with cancer progression and resistance of immunotherapy.

The clinical database was established at Loreus, United Kingdom and received data from all the clinical centres regarding the samples that were transferred to the scientific partners. The interface with OISTER and ESTDAB was also maintained. An audit of the clinical material accrued to date was carried out in summer 2006 and the relevant samples were sent to the necessary partners. Cell lines from the ESTDAB database were characterised for human leukocyte antigen (HLA) phenotypes.

The proteomics methodology was standardised for both serum and plasma proteins and peptides. Initial data was processed by bioinformatics and the validation of initial biomarkers and the identity of prominent proteins are now available. The melanoma material was used mainly for glycosylation studies, HLA loss studies, NK polymorphisms and serological studies.

A variety of immune assays were carried out on the clinical material provided to the ENACT project. Assays such as proliferation, cytotoxic T lymphocyte (CTL), enzyme-linked immunospot assay (ELISPOT), cytokine production were used by the partners involved in the work package and the results were submitted to the database at Loreus. Human MHC class I chain-related gene (MICA and MICB) expression was also assessed together with killer cell immunoglobulin-like receptor (KIR) polymorphisms in prostate and melanoma samples. A T7 phage display based SEREX approach was developed to assess the antibody repertoire initially in melanoma patients, with the intention of expanding the study into other cancer types.

The use of therapeutic cancer vaccines still has to be firmly established and previous clinical trials strongly indicate that not all patients benefit from such treatment. The present study allowed us to establish whether the results of ENACT will be beneficial in a clinical setting. The identification of indicators of patient response to immunotherapy would have an input on clinical practice, hence allowing clinicians to target vaccination to those individuals who are most likely to respond. The findings of the study would also result in assays being developed that could be used to predict treatment outcome and/or monitor patients during the course of treatment.

This approach allows the scientific community to gain further insight into the immune response to tumour antigens, which may influence the development of the future generation of cancer vaccines. This research would impact on the welfare of those patients who may be considered suitable candidates for vaccine-based therapy.