Active specific immunotherapy is an attractive strategy for patients with prostate cancer because this tumor is slow growing, potentially allowing time to augment host responses. Moreover, the available treatment options are limited to surgery and hormonal intervention with most tumors eventually becoming hormonal refractory. The studies proposed in this application are focused on generating host immune responses to prostate tumor cells and, in particular to prostate specific ,antigen (PSA), and to prostate specific membrane antigen (PSMA). As PSA and PSMA are immunogenic, produced by the majority of prostate cancer cells, and nearly exclusively expressed by prostate cells, they represent attractive targets separately and together for active specific immunotherapy of prostate cancer. Our approach is to use CD64 (FcyRI) targeted fusion proteins (FP) to deliver PSA and/or PSMA specifically to CD64 on antigen presenting cells (APC). Our previous studies, and those of other workers, have shown that targeting antigen via similar FPs significantly improves antigen presentation. In addition, FPs (H22xPSA) incorporating PSA and the humanized Fab portion of anti-CD64 could target CD64 expressing cells to process and present peptides in association with MHC class I for killing by cytolytic T lymphocytes specific for PSA peptides. Based on these findings, we propose studies in this application that would establish a coherent strategy for a phase I clinical trial to treat prostate cancer patients with metastatic disease. In particular, we would: 1) Evaluate the efficiency and extent to which targeting the tumor associated antigens PSA and PSMA to antigen presenting cells modulates MHC class I and II restricted T cell responses. We would develop FP constructed with anti-CD64 and whole tumor protein, and evaluate their ability to target appropriate processing and presentation by APC for generation of anti-tumor Th1 and CTL responses, and the relative efficiency and extent to which different FP target processing and presentation in association with MHC class I and/or Il; 2) Evaluate the mechanisms associated with enhanced processing and presentation resulting from targeting prostate antigens to FcyRI on antigen presenting cells, including the effects on antigen presenting cells, and in particular DC (i) of cytokines that enhance FcyRI expression and induce antigen presenting cell differentiation and maturation; (ii) of ligating CD40; and (iii) on the pathway of antigen presentation in association with MHC class 1; and 3) Using a murine model of human prostate cancer in mice transgenic for human FcyRI, we would examine the effects of targeting prostate antigens to FcyRI alone and in conjunction with immune modulators to determine the requirements for, and mechanisms of, induction of the most robust Th1 and CTL immune response to PSA and to PSMA and the extent to which this targeted vaccine approach is effective.
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