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Dissecting the therapeutic effects of anti-CTLA-4 and ADT in a murine hormone-sensitive prostate cancer.

61 Background: Immune checkpoint blockade with anti-CTLA-4 has emerged as a successful, novel form of cancer immunotherapy that acts directly on activated T cells instead of on cancer cells. CTLA-4 blockade can result in durable, long-term responses, but only a subset of patients treated benefit from this approach. Androgen deprivation therapy (ADT) is the first-line treatment for advanced prostate cancer, and it produces some of the most dramatic responses in clinical oncology. Clinically, the combination of ADT and anti-CTLA-4 was found to be more effective than ADT alone. To optimize the development of combination regimens, we examined the kinetics of the immune effects of ADT ± anti-CTLA-4 in a murine model of hormone-sensitive prostate cancer.


METHODS
Mice with established Myc-CaP prostate tumors were divided into 4 treatment groups: 1) untreated, 2) degarelix, 3) anti-CTLA-4, or 4) degarelix plus anti-CTLA-4. Tumor growth was measured biweekly. Tumor-infiltrating lymphocytes and T cell cytokine production was determined by flow cytometric analysis and serum IFN-gamma levels were assessed by ELISA.


RESULTS
We found that degarelix rapidly induces castrate levels of testosterone within 24 hours in mice and maintains these levels for at least 35 days. The combination of degarelix and anti-CTLA-4 improved median overall survival compared to degarelix alone (P<0.030, Mantel-Cox log-rank test). Tumor regression was associated with the production of the Th1-cytokines, IFN-gamma and TNF-alpha by tumor-infiltrating CD4+ and CD8+ T cells within 1 week of treatment initiation. This response peaked at 2 weeks after treatment initiation and was associated with elevated levels of serum IFN-gamma levels. In this model, anti-CTLA-4 monotherapy had no effect on tumor growth rates or intratumoral/sera cytokine levels.


CONCLUSIONS
The combination of immune checkpoint blockade with anti-CTLA-4 and medical castration with degarelix is therapeutically effective in a murine model of hormone-sensitive prostate cancer, likely through an IFN-gamma-dependent manner. This model can be used to better identify potential post-treatment biomarkers that can be studied for associations with clinical outcomes.