Increasing evidence suggests that leukemias and lymphomas have identifiable rearranged B or T cell receptor genes, unique chromosomal translocations, altered tumor suppressor genes, or modified heat shock protein which might serve as tumor antigens (Ag). The central thesis of this proposal is that human leukemia and lymphoma Ag exist, however, they are not effectively presented to Ag specific T cells to generate clinically significant anti- tumor cell responses. Inability to effectively present tumor Ag might be due to absence of: 1) appropriate adhesion molecules, 2) defects in cellular machinery to process and present Ag, 3) defects in the T cell receptor and its signaling, and/or 4) absence of appropriate critical costimulatory signals. Following effective adhesion and Ag processing, T cells require two signals which must be delivered by cells capable of presenting Ag. Signal 1 is both Ag and MHC restricted and is delivered to the T cell receptor. Signal 2 is neither Ag specific nor MHC restricted and results in T cell proliferation, cytokine secretion and effector function. Absence of signal 2 results in the generation of tolerance. Compelling in vitro and in vivo preclinical evidence in both murine and human systems suggests that the B7 family of costimulatory molecules provide one such critical signal 2. We propose that absence of B7 family mediated costimulation is responsible, at least in part, for the paucity of clinically significant T cell mediated immunity against leukemias and lymphomas. Preclinical studies in four tumor models supports this hypothesis. Transfection of the B7 gene into immunogenic tumors results in their rejection and confers long lasting tumor immunity to re-challenge with non-B7 transfected parental tumor cells. Therefore, the primary goal of the Project is to induce T cell antigen specific anti-leukemia/lymphoma mediated immunity by repairing defects in Ag presentation and inducing maximal critical costimulation. To this end, we propose four specific aims. First, we plan to develop an in vitro assay system to enumerate the frequency of Ag specific precursor helper (pHTL) and cytotoxic (pCTL) T lymphocytes to assess whether patients with leukemia or lymphoma have mounted Ag specific T cell mediated anti-tumor immune responses in vivo. Second, we plan to attempt to alter neoplastic cells to enhance T cell recognition of Ag by improving cellular adhesion, Ag presentation, and costimulation. Third, we plan to determine if normal individuals and tumor bearing hosts can respond to specific peptide tumor Ags presented by professional APC's. Fourth, we plan to attempt to reverse tumor specific T cell anergy in vitro. In another Project, we plan to begin to immunize selected patients with altered leukemia or lymphoma cells or peptide tumor Ags presented by professional APC in an attempt to alter the frequency of pHTL and pCTL in vivo. The success of this project is highly interdependent on identification and Ags, growth of neoplastic cells preclinical invivo studies and the availability of patients with leukemia and lymphoma for both tumor samples and translation to the clinic.
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