The adoptive transfer of immunologically sensitized T lymphocytes can eradicate established malignancy in animal models. However, inconsistent results have been achieved in clinical trials of adoptive immunotherapy. The applicant has focused on the isolation of therapeutic T cells from the tumor-bearing host, as this has direct relevance for translation of adoptive immunotherapy to human clinical trials. T cells can be isolated from lymph nodes draining a progressively growing tumor that are able to mediate the regression of tumor upon adoptive transfer. Recently he has identified a population of CD4 T cells that can mediate the regression of an established MHC class II negative tumor. These CD4 T cells are more potent on a per cell basis at tumor eradication than previously isolated tumor-reactive T cells. The hypothesis is that CD4 T cells are potent antitumor effector cells. This is explored by studying the development, therapeutic reactivity, and effector mechanisms of tumor-reactive CD4 T cells, as this knowledge may provide for improvements in human adoptive immunotherapy.
Specific Aim 1 studies the therapeutic reactivity of CD4 L-selectin- T cells against brain, lung, and subcutaneous tumors, and studies the role of CD28 and CD40L interactions in the development of these CD4 T cells. The CD4 L-selectin-T cells that can eliminate tumor secrete IL-2, IFN-g, and IL-10 upon stimulation with tumor, and therefore may either not be fully differentiated (Th0), or may be a mixture of Thl and Th2 type cells. Therefore, Specific Aim 2 investigates the ability of cytokine differentiated CD4 T cells and CD4 T cell clones to eradicate tumor, to further define the T cell that is responsible for tumor elimination. In bulk cultured lymph node T cells, IFN-g is required for elimination of tumor in the lungs, while perforin is required for the elimination of subcutaneous tumor. The effector molecules used by CD4 T cells to eliminate tumor have not been elucidated, and the contribution of perforin, IFN-g, and FASL to tumor eradication by adaptively transferred CD4 T cells is investigated in Specific Aim 3.
