Clinical Cancer Research: CCR-13-1026 Revision Combination Therapy with a Second-Generation Androgen Receptor Antagonist and a Metastasis Vaccine Improves Survival in a Spontaneous Prostate Cancer Model

Conflict of Interest: The authors have declared that no competing interests exist. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance This study examined whether the combination of anti-androgen therapy enzalutamide, plus a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis, could improve survival in TRAMP (transgenic adenocarcinoma of the mouse prostate) mice, a spontaneous prostate cancer model. Enzalutamide mediated immunogenic modulation in vitro, reduced genitourinary tissue weight, enlargement of the thymus, increased levels of T-cell excision circles in vivo. Because no changes were seen in T-cell function, as determined by CD4 + T-cell proliferation and Treg functional assays, enzalutamide was determined to be immune inert. Furthermore, enzalutamide did not diminish the Twist-vaccine's ability to generate Twist-specific immunity. The combination of enzalutamide and Twist-vaccine resulted in significantly increased overall survival of TRAMP mice compared to other treatment groups (27.5 vs. 10.3 weeks). Notably, the effectiveness of the combination therapy increased with disease stage, i.e., the greatest survival benefit was seen in mice with advanced-stage prostate tumors. These findings establish a rationale for the combined use of immunotherapy and anti-androgen therapy enzalutamide as a promising treatment strategy for CRPC. Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract Purpose: Enzalutamide, a second-generation androgen antagonist, was approved by the FDA for castration-resistant prostate cancer (CRPC) treatment. Immunotherapy has been shown to be a promising strategy for prostate cancer. This study is performed to provide data to support the combination of enzalutamide and immunotherapy for CRPC treatment. Experimental Design: Male C57BL/6 or TRAMP prostate cancer model mice were exposed to enzalutamide and/or a therapeutic vaccine targeting Twist, an antigen involved in epithelial-to-mesenchymal transition and metastasis. The physiological and immunological effects of enzalutamide were characterized. The generation of Twist-specific immunity by Twist-vaccine was evaluated. Finally, the combination of enzalutamide and Twist-vaccine to improve TRAMP mice overall survival was evaluated. Results: Enzalutamide mediated immunogenic modulation in TRAMP-C2 cells. In vivo, enzalutamide mediated reduced genitourinary tissue weight, enlargement of the thymus, and increased levels of T-cell excision circles. Because no changes were seen in T-cell function, as determined by CD4 + T-cell proliferation and Treg functional assays, enzalutamide was determined to be immune inert. Enzalutamide did not diminish the Twist-vaccine's ability to generate Twist-specific immunity. Twist was confirmed as a valid tumor antigen in TRAMP …