Abstract 3208: Chemo-induced biology of PD-L1 and in vivo combination immune therapy for ovarian cancer
Authors: Grabosch Shannon , Zeng Feitianzhi , Zhang Lixin , Ma Tianzhou , Tseng George , Edwards Robert P. , Vlad Anda M. 
Published: July 2016

Rationale: Ovarian cancer patients receive platinum/taxane-based chemotherapy as standard of care. Five year survival has remained unchanged for several decades, at less than 45%, pointing to the need for new and improved therapies. We recently reported in vivo anti-tumor efficacy of PD-L1 immune checkpoint blockade in a new transplantable ovarian cancer mouse model. However, chemo-induced effects on ovarian tumor PD-L1 expression have not been addressed. We studied here the effect of platinum/taxane on tumor PD-L1 expression in vitro and in vivo and tested the efficacy of PD-L1 blockade in combination with cisplatin, using several treatment regimens.

Methods and Results: Our results demonstrate that in vitro exposure of several human ovarian cancer cell lines, with various baseline susceptibilities to cisplatin and taxol, triggers PD-L1 upregulation. Similar effects were observed when newly tumor-derived, platinum sensitive (2F8) and platinum resistant (2F8cis) murine ovarian cancer cell lines were exposed to chemo drugs in vitro. Based on these findings we postulated that PD-L1 immune checkpoint blockade in combination with cisplatin may provide therapeutic benefit in ovarian cancer. In vivo, we have challenged n = 37 mice IP with 0.8 million 2F8 cells. Tumor-bearing mice were treated with cisplatin, anti-PD-L1 antibody, both drugs or isotype control every two weeks for three doses starting at day 14 post-inoculation. Study endpoint was overall survival. Secondary endpoints were tumor CD8 infiltration, changes in Th1/cytotoxic immunity. Tumors and ascites-derived cancer cells were analyzed with flow cytometry. RNA was extracted from splenocytes and analyzed with Nanostring using probes for n = 511 immune genes.

In line with in vitro results, tumor cells isolated ex vivo from cisplatin-treated mice expressed increased PD-L1. Compared to control treated mice, both Cisplatin alone and anti-PD-L1 alone increase overall survival (p = 0.002 and p = 0.02, respectively). No increase in survival was observed in anti-PD-L1/Cisplatin-treated mice, due to an over-responsive immune cascade overwhelming the animal. Addition of celecoxib, a cyclooxygenase-2 inhibitor, to the anti-PD-L1/cisplatin combination was well tolerated and led to improved overall survival.

Conclusion: Ovarian cancer cells upregulate PD-L1 in response to chemotherapy exposure in vivo and in vitro. Though effective independently, combination cisplatin and anti-PD-L1 blockade did not improve survival, likely due to cytokine release syndrome. Celecoxib added to cisplatin and anti-PD-L1 improves overall survival. Anti-tumor immunity in responder mice revealed a cytotoxic T cell mediated gene signature. These findings reveal benefits and pitfalls of chemotherapy in combination with immune checkpoint blockade and have high translational potential for ovarian cancer treatment.

Citation Format: Shannon Grabosch, Feitianzhi Zeng, Lixin Zhang, Tianzhou Ma, George Tseng, Robert P. Edwards, Anda M. Vlad. Chemo-induced biology of PD-L1 and in vivo combination immune therapy for ovarian cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3208.