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ENACT<br />
European Network for<br />
the identifi cation and validation<br />
of antigens and biomarkers<br />
in cancer and their application in<br />
clinical cancer immunotherapy<br />
Summary<br />
Prospective clinical material will be collected during the life<br />
of the programme and new and existing tumour tissue, PBMC<br />
and serum banks will be available for use in the study. This<br />
common resource of material will be distributed to partners<br />
for the immunological, genomic, biochemical and proteomic<br />
analysis of tumour and host response(s) to immunotherapy.<br />
The results will be subjected to bioinformatic analysis in<br />
the context of clinical outcome of vaccine-based immunotherapy<br />
trials from fi ve European clinical centres. Analysis of<br />
the results in the context of gender will allow prominent<br />
inter- and intra-tumour/host biomarkers to be identifi ed for<br />
translation back into clinical practice.<br />
Problem<br />
Keywords | Tumour progression | biomarkers | tumour escape | melanoma | prostate cancer | ovarian cancer |<br />
<strong>Cancer</strong> remains a major health problem, with untold physical,<br />
psychological and economic costs to society. Elimination<br />
of cancer would reduce health care costs and enhance<br />
quality of life. Along with cardiovascular disease and ageing,<br />
it is currently the most intractable source of suff ering<br />
and health care cost. Recent results from immunotherapy<br />
trials would suggest that inducing tumour-specifi c T-cell<br />
responses to tumour antigens can, in some patients, cause<br />
the regression of tumours or the stabilisation of the disease.<br />
However the mechanisms underlying the failure of immunotherapy<br />
to control and destroy residual cancer remains to<br />
be fully established. Experimentally, it can be shown that<br />
tumour rejection is mediated by CD8+CTLs aided by<br />
CD4+Thelper cell activity. However animals that fail to<br />
respond may fail to demonstrate a pronounced (if any) CTL<br />
response. In addition data from many laboratories have<br />
shown that tumour escape from CTLs can occur as a result<br />
of downregulation of MHC class I antigens, and in some<br />
instances cancer cells that show successive mutations may<br />
demonstrate progressive and complete loss of MHC expression.<br />
The current status of our understanding of adoptive<br />
cancer immunity also suggests that immune tolerance can<br />
equate with lack of response, with possible regulation by<br />
CD4+CD25+T-lymphocytes as well as other regulatory cells.<br />
Breaking tolerance through immunotherapy therefore represents<br />
one possible approach to promote T-cell responses<br />
and tumour regression.<br />
Aim<br />
ENACT aims to identify markers of response and tumour<br />
antigens that associate with ovarian, breast and prostate<br />
cancer and melanoma progression and resistance to immunotherapy.<br />
The present application will address these issues<br />
in a number of ways and directly analyse the important<br />
biomarkers that are expressed by cancer and may therefore<br />
be considered as novel targets by establishing a European<br />
network for collaboration. The cancer types to be included<br />
will address the issue of sex-related biomarkers associating<br />
with resistance to therapy. Cell biological, immunological,<br />
biochemical and molecular biology-based technologies will<br />
be used and knowledge generated in this project will not<br />
only result in a desired and highly competitive technological<br />
base for vaccine development (not necessarily restricted to<br />
cancer vaccines), but also will provide a better understanding<br />
of basic biological mechanisms underlying antigen<br />
presentation and recognition of tumours by CD8+ and CD4+<br />
T lymphocytes and NK cells.<br />
Expected results<br />
• To establish a database for the analysis of clinical and<br />
experimental results in order to identify markers related<br />
to the outcome of immunotherapy.<br />
• To provide clinical material and cancer cell lines for scientifi c<br />
investigation conducted within the programme.<br />
• To assess the cellular and humoral immune response in<br />
patients undergoing immunotherapy.<br />
• To identify biomarkers using proteomics and computer<br />
based algorithms.<br />
• Assessment of the importance of immunological, genetic<br />
and proteomic biomarkers as indicators of therapeutic<br />
response related to gender.<br />
• Dissemination of the information to the scientifi c community<br />
and the community at large.<br />
194 CANCER RESEARCH PROJECTS FUNDED UNDER THE SIXTH FRAMEWORK PROGRAMME
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