Blockade of inhibitory molecules on T cells has been shown to be an effective Immunotherapy strategy to treat cancer. The prototypic inhibitory molecule is CTLA-4, which is induced upon T cell activation and acts to inhibit proliferation. We hypothesized that although CTLA-4 is necessary to maintain homeostasis and prevent autoimmune responses, it might also limit effective anti-tumor immune responses. We developed anti-CTLA-4 and used it to successfully treat tumors in murine models. Our data were translated to the clinic and a phase 3 trial with anti-CTLA-4 was recently shown to lead to durable regression of disease and survival benefit in some patients with metastatic melanoma. Because anti-CTLA-4 therapy is not tumor specific, and phase 1 and 2 clinical trials have demonstrated a clinical response in patients with prostate cancer, a phase 3 clinical trial is currently accruing patients with metastatic castration-resistant prostate cancer (CRPC).
Our specific aims are as follows: 1. To determine the effects of immune checkpoint blockade and targeted therapies on immune function and anti-tumor responses, a) To determine quantitative changes in immune cell subpopulations of wild-type mice following treatment, b) To determine changes in antigen-specific T cell functions using adoptive T cell transfer, c) To optimize anti-tumor responses in murine prostate cancer models using combinations of targeted therapy and immune checkpoint blockade. 2. To determine the role of sB7-H3 and sB7-H4 in prostate cancer, a) To assay patient serum samples for SB7-H3 and sB7-H4 and correlate levels with disease status, b) To determine the immunomodulatory effects of SB7-H4 in vitro. 3. To determine whether CTLA-4 blockade in CRPC results in detectable immunological changes that correlate with clinical outcomes, a) To assess antibody responses against tumor antigens in treated patients, b) To assess ICOS (inducible co-stimulator) expression on T cells in treated patients, c) To assess serum levels of SB7-H3
Current treatments for prostate cancer are inadequate in that responses are usually not durable. Therapies that target the AR and PISK pathways more efficiently (ARN-509 and BEZ235) are perhaps the most promising non-immunotherapeutic agents in development for prostate cancer.
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