The goal of this project is to develop methodology to induce melanoma specific cytotoxic T lymphocyte (CTL) immunity using defined peptides. To accomplish this we will first identify melanoma specific peptides which are presented in association with class I MHC molecules to melanoma specific CTLs. These peptides will be extracted from melanoma cells, fractionated, and then identified by their ability to stimulate melanoma specific, class I restricted T-T hybridomas or CTL clones. Once identified, these peptides will be used to develop methods for priming melanoma specific CTLs in vivo. We will exploit the observation that the receptivity of cell surface class I MHC molecules for exogenous peptide can be increased significantly in the presence of exogenously added beta2-microglobulin. We will develop vaccination techniques by introducing peptide and beta2M in a manner that will form peptide-class I MHC molecule complexes capable of priming CTLs in vivo. These techniques will be developed in murine and human class I MHC restricted systems. Methodology developed through this proposal would provide significant advances in melanoma immunotherapy. First, we will develop techniques to expand melanoma specific CTLs from tumor infiltrating lymphocytes or blood- born lymphocyte populations in vitro, augmenting current adoptive immunotherapy protocols. Second, peptide vaccination strategies developed by these investigations would prime melanoma CTL immunity in vivo, providing several potential advantages over existing forms of melanoma immunotherapy. Laboratory training sponsored by this award will primarily occur within the Division of Lymphocyte Biology at the Dana Farber Cancer Institute with the guidance of Dr. Kenneth Rock and Dr. Baruj Benacerraf. The overall training program will include didactic, laboratory, and clinical components utilizing the resources of the Dana Farber Cancer Institute, Harvard Medical School, and the Harvard Department of Dermatology.
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