Research objectives and content
A number of antigens have been identified on human tumors that are recognised by autologous cytotoxic T lymphocytes (CTL). Some of these antigens are encoded by MAGE genes, that are specifically expressed in a wide range of tumors. MAGE-encoded peptides are currently used for immunisation protocols of melanoma patients to induce specific anti-tumor immunity and subsequent tumor rejection. However, only patients that express the MAGE gene in combination with the relevant HLA type are eligible for the immunisation with the currently known peptides. Identification of new peptides that bind other HLA types will therefore allow more patients to benefit from immunisation with specific peptides. In addition, immunisation can be performed with multiple peptides, which may improve the immunisation efficacy.
Specific helper T lymphocytes are important for the induction and maintenance of a cytotoxic T lymphocyte response in vivo. Immunisation with a combination of HLA class I and class II-restricted peptides may activate both CTL and helper T lymphocytes and, therefore, enhance the efficacy of an anti-tumor response.
We intend to identify new antigenic peptides encoded by MAGE genes, that are recognised by cytotoxic T lymphocytes or by helper T lymphocytes. Since MAGE genes encode large proteins, new peptides may be identified in these proteins that bind other HLA class I or class II molecules. For this purpose, dendritic cells will be loaded with the recombinant MAGE protein, or MAGE genes will be expressed in dendritic cells by pox virus-mediated gene transfer. The dendritic cells will be used to prime T lymphocytes, that are subsequently tested for peptide recognition in cytotoxicity assays or cytokine production assays or cytokine production assays. Training content (objective, benefit and expected impact)
A postdoctoral training at the Cellular Genetics Unit of the ICP will provide me with the possibility to gain experience in tumor immunology with respect to specific anti-tumor T cell responses and to learn the techniques. The Cellular Genetics Unit of the ICP has pioneered these techniques in the past, and therefore represents an excellent place to acquire this experience. The development of cancer vaccines is one of the major research aims in tumor immunology, and will remain an area of importance now that clinical studies have started. This training will allow me to work on cancer vaccines-related project in The Netherlands in the future.
Links with industry / industrial relevance (22)
Recombinant proteins for several tumor antigens such as MAGE-3 will be used for in vitro loading of antigen-presenting cells. This recombinant protein has been produced by the Smith Kline Corporation pharmaceutical company. MAGE-3 is already available for in vitro studies. This protein will be available for clinical trials organized in several European clinical centers. Recombinant poxviruses will be produced for clinical trials by Virogenetics & Pasteur-Merieux. Recombinant ALVAC-MAGE-1 and a Vaccinia-MAGE-1 are already available for in vitro use.