The goal of the proposed project is to develop methods to stimulate and grow melanoma-reactive T cells from individuals with malignant melanoma and to identify and characterize the antigens recognized. Principles have been developed in animal models for the eradication of established malignancy by use of the adoptive transfer of T cells reactive to the tumor. One of the prerequisites for successful therapy is the availability of large numbers of tumor-reactive T cells. However, the limited therapeutic efficacy of small numbers of tumor-reactive T cells can be greatly augmented by growing the T cells in vitro and treating with the increased number of T cells. Numerous research groups have demonstrated that small numbers of melanoma- specific T cells exists in patients with melanoma. Moreover, attempts to treat melanoma with regiments designed to function, in part, by increasing the number of melanoma-reactive T cells--either by active immunization with melanoma-associated antigens, or by the adoptive transfer of melanoma- specific T cells generated in vitro--have met with substantial success in a small but definite proportion of the patients treated. Extrapolating from animal models, two major problems inhibiting a more successful application of specific adoptive immunotherapy to human melanoma are in adequate culture systems for generating large number of T cells with retention of the ability to proliferate in response to tumor, and inadequate identification of the antigens recognized by autochthonous melanoma- specific T cells. Both problems are potentially solvable by focusing on CD4+ T cells, as opposed to CD8+ T cells. Since CD4+ T cells are class II MHC-restricted, CDR+ T cells can be stimulated to proliferate in vitro in response to tumor or in response to soluble tumor antigen. By contrast, CD8+ T cells are class I MHC-restricted and therefore only respond to antigen synthesized within the presented by intact tumor cells. Thus, CD4+ T cells are easier to grow long-term with retention of specificity, specificity is easier to validate, and the antigens recognized are exceedingly easier to identify and characterize by currently available technology. In addition, tumor-specific CD4+ T cells have been shown to be extremely effective when utilized alone in specific tumor therapy in some animal models, and are potentially capable of mediating tumor eradication by direct lysis of tumor and by secretion of a variety of lymphokines that can directly and/or indirectly destroy tumor cells.
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