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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Type
Specialized Center (P50)
Project #
5P50CA092629-14
Application #
8730088
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
14
Fiscal Year
2014
Total Cost
Indirect Cost
City
New York
State
NY
Country
United States
Zip Code
10065
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