Dabigatran and Cisplatin Co-Treatment Enhances the Antitumor Efficacy of Immune Checkpoint Blockade in A Murine Model of Resistant Ovarian Cancer

Abstract

and Cisplatin Co-Treatment Enhances the Antitumor Efficacy of Immune Checkpoint Blockade in A Model of Resistant Ovarian Cancer. Abstract The standard treatment for ovarian cancer is surgical debulking followed by platinum- taxane-based chemotherapy. Although most patients are initially responsive to this therapy, patients in advanced stages eventually relapse and die. New therapeutic approaches using immune checkpoint blockade (ICB) have been less promising in ovarian cancer compared to other tumor types, resulting in durable tumor regression in only a small subset of ovarian cancer patients. Because previous studies showed immunomodulatory effects following co-treatment with cisplatin and the thrombin inhibitor dabigatran etexilate (C/D) in a preclinical animal model of ovarian cancer, we explored to what extent this co-treatment may enhance the anti-tumor efficacy of ICB in the ID8 tumor model that is resistant to ICB. Whereas cisplatin or dabigatran treatment alone or co-treatment with cisplatin and anti-PD-1 monoclonal antibody (mAb) demonstrated little significant effect on tumor spread, co-treatment with C/D with or without anti-PD-1 mAb significantly reduced ID8 tumor burden and increased peritoneal INF-γ producing CD8+ T-cells after only 2 weeks of treatment. Moreover, C/D cotreatment with ICB conferred a durable survival advantage over C/D or ICB alone. The enhanced anti-tumor effect and survival with C/D co-treatment and ICB compared to that with C/D or ICB alone was accompanied by decreases in immunosuppressive M2- macrophages, decreases in pro-tumorigenic cytokines, and corresponding increases in tumor-infiltrating, IFN-γ-producing CD8+ T-cells. Our findings provide proof-of-concept evidence that the addition of ICB with thrombin inhibition in frontline platinum-based chemotherapy may be a potential new therapeutic treatment combination for advanced ovarian cancer.