THE USE OF MELANOSOMAL PROTEINS IN THE IMMUNOTHERAPY OF MELANOMA

Clinical observations in the interleukin (IL) 2-based immunotherapies suggest that T cells play a central role in the rejection of melanoma. Using cDNA expression cloning, we have isolated genes encoding melano ma antigens recognized by tumor-infiltrating T lymphocytes. These anti gens are categorized as (a) melanocyte specific melanosomal proteins ( MART-1/meian A, gp100; tyrosinase, TRP-I, and TRP-2), (b) tumor-specif ic mutated proteins (beta-catenin), and (c) others (p15). A variety of mechanisms has been identified for the generation of T cell epitopes on tumor cells. Some of the HLA-A2 binding epitopes from the melanosom al antigens appear to be subdominant self-determinants with relatively low major histocompatibility complex binding affinity. The effectiven ess of adoptive transfer into patients of cytotoxic T lymphocytes reco gnizing the melanosomal antigens, the significant correlation between vitiligo development and clinical response in patients receiving IL-2- based immunotherapies, and the sporadic tumor regressions observed in some patients following immunization with the MART-1 or gp100 peptides in incomplete Freund's adjuvant or recombinant viruses expressing the MART-1 antigen suggest that these epitopes may represent tumor reject ion antigens. Phase I immunization trials using peptides or recombinan t viruses containing genes encoding the melanosomal antigens MART-1 or gp 100, with or without co-administration of cytokines such as IL-2, IL-12, or granulocyte-macrophage colony-stimulating factor, are being conducted in the Sur gery Branch of the National Cancer Institute. The se studies may demonstrate the feasibility of using melanosomal protei ns for the immunotherapy of patients with melanoma.