Abstract B51: Synergistic effects of αCTLA-4 and radiotherapy in the treatment of prostate cancer.

Abstract

Abstract Objective: External Beam Radiation Therapy (EBRT) in combination with androgen deprivation therapy (ADT) is the standard treatment for high risk, non-metastatic prostate cancer but frequently fails to provide durable responses. It causes tumor necrosis and tumor antigen presentation to the immune system with subsequent activation of T cells, a phenomenon that is inhibited by CTLA-4. As a result, CTLA-4 blockade therapy has the potential of enhancing effector T cell responses and therefore, improving treatment effectiveness and patient outcomes. CTLA-4 blockade therapy utilizing anti-CTLA4 antibodies has been studied in patients with metastatic, castrate resistant prostate cancer with promising results. However, the role of such therapy in combination with ADT and EBRT in high-risk, non-metastatic prostate cancer is currently unknown. In this study, the safety and efficacy of CTLA-4 blockade in combination with EBRT and ADT was investigated in a syngeneic murine prostate tumor model. Materials and Methods: TRAMP-C2 prostate tumors were established in wild-type mice for 1 month prior to surgical castration. Mice were stratified into 3 groups. Group 1: Two weeks after castration, tumors were radiated with 3 doses of 10 Gy over a period of 10 days. Group 2: Mice received 3 x 10 mg/kg doses of αCTLA-4 (9H10) daily, starting 2 or 10 days after castration. Group 3: Mice received αCTLA-4 (3 x 10 mg/kg) concurrently with radiation treatment. Peripheral blood was monitored weekly for changes in T cell subsets. Tumor growth, survival, toxicity and reactivity to a H2-Db epitope of SPAS-1 were also assessed. Results: There were no αCTLA-4 treatment-related morbidity or mortalities. αCTLA-4 started at 10 days after castration, or concurrently with radiation had a longer median survival (127 days and 122.5 days, respectively) compared to mice receiving αCTLA-4 earlier (72.5 days median survival). Mice that only received castration and radiation had a median survival time of 70 days. In addition, an increase in antigen experienced CD8+ T cells was detected in mice receiving αCTLA-4 closest to or during radiation therapy. Recall assays indicated that SPAS-1 specific T cells were only detectable in αCTLA-4 treated mice. Two weeks after radiation, there was also a 2-fold increase in ICOS+ CD4+ T cells in mice that had been treated with αCTLA-4 immediately prior to radiation as compared to those that had been treated immediately after castration. Conclusions: Administration of αCTLA-4 close to, or during EBRT in combination with ADT delays tumor growth and improves survival in the TRAMP-C2 prostate cancer tumor model in part through increases in antigen specific CD8+ T cells. Future studies will further elucidate the mechanism of action of this combined therapy and pave the way for the development of clinical trials in high risk prostate cancer patients. Citation Format: Lisa DS Johnson, Wayne A. Beckham, Gordon H. Russell, Julian J. Lum, Maria T. Vlachaki. Synergistic effects of αCTLA-4 and radiotherapy in the treatment of prostate cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr B51.