Effect of androgen deprivation therapy combined with nivolumab on the systemic antitumor immune response in castration-sensitive prostate cancer.

Abstract

e17503 Background: To date, immunotherapy has limited efficacy in castration-resistant prostate cancer. However, we previously reported that androgen deprivation therapy (ADT) has significant immunomodulatory effects and can induce a complex immune cell infiltrate before castration-resistance develops. Therefore, we designed an ongoing clinical trial to assess the effects of immunotherapy plus ADT in men with recurrent castration-sensitive prostate cancer (CSPC) (NCT03689699). We hypothesized that PD-1 blockade given at the time of castration could induce systemic anti-tumor immune responses with epitope spreading and modulate key circulating cytokine networks. Methods: 15 patients with recurrent CSPC were treated with nivolumab (480mg) every 4 weeks for 8 weeks followed by nivolumab plus degarelix for an additional 16 weeks. Sera was collected at 3 time points: pre-treatment, after nivolumab alone (8 weeks) and at completion of therapy with nivolumab plus degarelix (24weeks). To assess the therapeutic effects on systemic humoral immune responses and to evaluate for induction of epitope spreading, we analyzed treatment-induced serum IgGs against an array of self-antigens over time. We also performed a 44-parameter electrochemiluminescence assay to measure the effects of therapy on innate cytokines and the Th1/Th2 and Th17 pathways. Results: ADT combined with PD-1 blockade led to significant changes in systemic immunity including induction of humoral antigen spread with IgG responses to secondary tumor antigens including PSA, KLK2, K-Ras and modulation of key circulating cytokines. We observed a significant increase in mean levels of IFN-gamma (8.68 +/- 10.74 pg/ml vs 9.53 +/- 7.36 pg/ml), an increase in IL-10 (0.37 +/- 0.29 pg/ml vs 0.66 +/- 0.53 pg/ml) and a decrease in IL-8 (106.7 +/- 275.47 pg/ml vs 25.49 +/- 23.09 pg/ml) when comparing cytokine levels before and after nivolumab plus degarelix respectively. Conclusions: ADT plus nivolumab led to significant changes in systemic immunity and overall appeared to promote a pro-inflammatory state. This immune response also appeared tumor specific with induction of humoral responses against secondary tumor antigens. However we also observed changes in targetable immunosuppresive cytokines like interleukin-8 and are currently testing whether ADT plus combined PD-1 and IL-8 blockade can further promote robust anti-tumor immune responses in prostate cancer. Clinical trial information: NCT03689699 .