T-cell mediated responses are known to play a key role in defense against cancer. A major current challenge is to devise strategies for generating specific antitumor immunity. Studies indicate the induction of T cell immunity or stimulation of pre-existing immunity is most likely to occur when antigens are presented to CD8+ or CD4+ T lymphocytes by MHC class 1 or class II molecules, respectively, that are expressed on the surface of """"""""professional"""""""" antigen presenting cells, particularly dendritic cells (DC). The tumor-reactive T-cells obtained from patients with cancers have been successfully used as biologic probes for purification of tumor- derived peptides. The goal of this proposal is to identify oral tumor peptides which can prime T-cell responses in vitro and which represent candidate peptides for future vaccinations of patients with oral squamous cell carcinoma (OSCC) and/or of individuals at high risk of developing oral tumors. Three types of strategies for preparation of vaccines for OSCC will be evaluated, all based on the hypothesis that immunogenic peptides can be derived from intracellular proteins processed and expressed by OSCC cells. The first strategy will aim at the isolation and identification of peptides associated with the MHC class I molecules expressed on autologous OSCC, using MHC class I-restricted (CD3+CD8+) T- cell lines as a reporter system. The second strategy depends on the use of an available autotumor-reactive, MHC class II restricted CD3+CD4+ T-cell line to identify. the OSCC-derived protein expressing immunogenic epitopes. The third strategy will use peptides eluted with acid from allogeneic HLA-A2+, -A3 and-B7+ OSCC cell lines for generation of anti- OSCC CTL in the presence of HLA-matched DC. It is expected that availability of these purified tumor-derived peptides and proteins will be an important first step in the development of potentially useful vaccines for active specific immunotherapy of patients with OSCC. A pilot phase I trial of a vaccine composed of autologous DC pulsed with autotumor-derived peptides will be designed to test its safety for patients with OSCC.
Showing the most recent 10 out of 94 publications
