Revised Abstract: Human tumor immunology has been advanced by the identification of antigens and the corresponding tumor specific lymphocytes, particularly killer and helper T-cells. This program will exploit the dendritic cell [DC] to enhance presentation of melanoma antigens to T-cells, primarily in humans but also in mouse models. Our impetus is 3 fold: (1) DCs can be generated in large numbers ex vivo from different precursor populations; (2) MHC class I and II products on DCs can be charged with an array of tumor antigens by feeding apoptotic and necrotic cells; (3) antigen-bearing DCs can rapidly boost the human immune system in situ. Therefore an integrated program in Dallas and New York can begin to actively immunize patients to melanoma antigens, concommitant with laboratory studies to learn to enhance DC processing of tumor antigens, to evaluate the roles of distinct DC subsets and maturation states, and to observe DC function in tumors and lymph nodes in situ. This program emphasizes melanoma, because tumor-specific T-cells are known for mice and humans, and it is now evident that DCs can present in vitro melanoma antigens derived from apoptotic cells. Documentation of tumor-specific immunity in humans has become more accessible with quantitative assays that are in place and include: binding of MHC-tetramers, production of ELISPOTS, and recall assays to elicit specific killer T-cells. The program will include two dual center randomized trials. In the first we will compare two types of DC in eliciting immunity to melanoma peptides, and look for spreading of the immune response to other antigens, as an index of cross presentation in vivo. In the second, we will compare DCs loaded with peptides vs. dying tumor cells in expanding tumor specific CD4 and CD8 T-cells. Shared ongoing core facilities for administration, DC production, and immune monitoring will energize and standardize interactions. Together, we hypothesize that DCs, nature's adjuvant, will enhance immunity to tumor antigens so that the clinical consequences for cancer vaccination and therapy can be pursued. COLLABORATING INSTITUTION(S) Arizona Cancer Center, Tucson, Arizona Baylor Research Institute, Dallas, Texas Institute Curie, Paris, France Memorial Sloan Kettering Cancer Center, New York, New York University of Texas, Southwestern Medical Center, Dallas, Texas.
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