Abstract 267: Combining androgen deprivation with immune checkpoint blockade delays the development of castration resistance in a murine model of prostate cancer
Authors: Shen Ying-Chun , Kochel Christina , Francica Brian J. , Alme Angela , Nirschl Christopher , Nirschl Thomas , Bujanda Zoila Areli Lopez , Carrera H Maria A. , Selby Mark , Korman Alan , Drake Charles G. 
Published: August 2015

Abstract
Androgen deprivation therapy induces immune cell infiltration in human prostate cancer. These findings suggest that immunotherapy may be most efficacious when administered concurrently with androgen deprivation, early in disease progression. We used a subcutaneous allograft model of murine prostate cancer (Myc-Cap), which mimics the development of human castration-resistant prostate cancer (CRPC) progression to study the anti-tumor effects of concurrent hormonal/immunotherapy. Implanted Myc-Cap tumors initially respond to androgen deprivation (degarelix acetate or bilateral orchiectomy), but mice eventually progress with CRPC. To test the hypothesis that the combination of androgen deprivation and immune checkpoint blockade could mediate pre-clinical benefit, we treated mice with either anti-PD-1, a depleting anti-CTLA-4 antibody (IgG2A), a non-depleting anti-CTLA-4 antibody (IgG1 D265A) or antibody combinations in the peri-castration period, then followed mice for the development of castration-resistant disease. Interestingly, the depleting anti-CTLA-4 antibody with/without anti-PD-1 antibody was strikingly effective in preventing the emergence of castration-resistant disease. The median castration-resistance free survival was 22 days in mice treated with androgen deprivation alone versus 32 days in mice treated with androgen deprivation and depleting anti-CTLA-4 antibody (P&lt;0.05, compared to androgen deprivation alone) versus 30 days in mice treated with androgen deprivation, depleting anti-CTLA-4 and anti-PD-1 (P&lt;0.05, compared to androgen deprivation alone; non-significant, compared to androgen deprivation and depleting anti-CTLA-4 antibody). Immunologically, we found that castration increases intratumoral infiltration of helper, cytotoxic and regulatory T cells (Tregs), natural killer cells, and macrophages, as well as effector cytokine production of T cells. We also found up-regulated expression of CTLA-4 and PD-1 as well as their respective ligands. Mechanistic studies showed that androgen deprivation combined with depleting anti-CTLA-4 /anti-PD-1 significantly reduces intratumoral Tregs and increases interferon-γ- or tumor necrosis factor-α- producing T cells in the tumor and its draining lymph node. In conclusion, while androgen deprivation renders the tumor microenvironment more immunogenic; the combination of androgen deprivation and depleting anti-CTLA-4 antibody with/without anti-PD-1 can significantly delay the development of CRPC.
Citation Format: Ying-Chun Shen, Christina Kochel, Brian J. Francica, Angela Alme, Christopher Nirschl, Thomas Nirschl, Zoila Areli Lopez Bujanda, Maria A. Carrera H, Mark Selby, Alan Korman, Charles G. Drake. Combining androgen deprivation with immune checkpoint blockade delays the development of castration resistance in a murine model of prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 267. doi:10.1158/1538-7445.AM2015-267