Research objectives and content
Several antigens have been identified that are recognized on human tumors by autologous cytolytic T lymphocytes (CTL). Many of these antigens are encoded by MAGE genes that are very selectively expressed by tumor cells. Therefore it is now reasonnable to try to immunize cancer patients against such tumor antigens to induce tumor rejection. Nevertheless, patients would be eligible for such immunotherapy only if their tumor cells express the relevant HLA molecule together with the gene coding for the antigenic peptide.
We intend to find new antigenic peptides encoded by the MAGE genes, in order to allow more patients to benefit from antitumor vaccines containing these antigens. Because some of these MAGE genes code for large proteins, we expect that some peptides corresponding to several regions of these proteins can combine with other HLA molecules to form antigens for anti-tumor CTL. A first strategy consists in searching the protein sequences for peptides containing HLA binding motifs, testing their binding in vitro to the relevant HLA molecule, and using the best candidates to stimulate T lymphocytes. An alternative method is to transfect dendritic cells or to load them with recombinant protein, and use these modified dendritic cells to induce primary antigen-specific CTL response in vitro. Advantages of this strategy include the covering of a complete protein with fewer experiments, and a more physiologic selection of the CTL epitopes by the antigen-presenting cells themselves. Training content (objective, benefit and expected impact)
The first objective of this training is learning techniques in molecular and cellular immunology in order to be able to identify potential tumor specific antigens. The Cellular Genetics Unit of the ICP have pioneered these techniques in the past and seems to me a very good place for postdoctoral training in tumor immunology. The development of efficient in vitro-priming protocols would be a new tool for many tumor models, and I will then be able to apply these techniques in other institutions. The possibility for me to pursue my postdoctoral position in the Cellular Genetics Unit will let me time enough to bring this project to issue and finally will offer me the best chances to get a position in a research institution like INSERM on my return to France.
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 will be produced within one year by the Smith Kline Corporation phamarceutical company. This protein will also be available for clinical trials organized in several european clinical centers.