A central problem in cancer immunology is to devise how tumor antigens could be made to stimulate and activate immune responses. Most tumor antigens are self-antigens and likely to induce immune tolerance unless they are appropriate presented to the immune system. Dendritic are the most potent antigen-presenting cells. They can stimulate and activate helper and cytotoxic T cells when precursor T cells are quiescent and present at low frequencies, a situation that applies to tumor-reactive lymphocytes. Gene transfer into dendritic cells offers the potential (a) to optimize selection and presentation of multiple antigenic epitopes restricted by various MHC alleles; (b) to facilitate presentation of both MHC class I and II-restricted epitopes; and (c) to support sustained antigen expression by dendritic cells. The goal of this project is to exploit the power of dendritic cells to present tumor antigens for the generation of effective cellular immunity against melanoma, in the following specific aims: I. How do human dendritic cells transduced with tumor antigens most effectively stimulate autologous T cell responses against cancer? II. Does the type of tumor antigen expressed in dendritic cells or the use of an artificially engineered antigen-presenting cell alter the immunologic responses against a tumor? III. Can dendritic cells transduced with gens encoding syngeneic or heteroclitic xenogeneic tumor differentiation antigens, and with genes encoding factors critical to dendritic cell growth and activation, induce tumor immunity in mouse melanoma models? IV. To what extent are human dendritic cells transduced with genes encoding melanoma antigens immunogenic when administered as vaccines to stage III/IV melanoma patients? Melanoma has been selected as the tumor model, because this tumor has defined antigens with known MHC restrictions. Immunity against human cancer, usually directed against differentiation antigens, has also been best characterized in melanoma patients. Data from this project should therefore support a broader use of gene-transduced dendritic cells as immunotherapeutic adjuvants to the treatment of most human cancers, where the tumor antigens and restricting MHC determinants will eventually be defined.
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