Abstract B01: Optimizing chemotherapy for the integration of immune therapy in ovarian cancer: Enriching effector T cells in the peritoneal tumor microenvironment using the route of cisplatin administration (IV vs. IP)
Authors: De May Henning S. , Desai Sharina Palencia , Kinjyo Ichiko , Adams Sarah F. 
Published: September 2020

Abstract
Background/Objective: Despite its success in treating other tumor types, immune therapy has underperformed in ovarian cancer. One reason may be the residual effects from prior treatment. Standard therapy of ovarian cancer includes surgery and platinum-based chemotherapy administered intravenously (IV) or intraperitoneally (IP). IP cisplatin results in higher concentrations of drug in the peritoneal cavity compared to IV. With evidence from our lab that peritoneal lymphocytes have a significant impact on treatment efficacy in ovarian cancer models, we sought to determine the impact of the route of cisplatin administration on local T-cell subsets. Our long-term goal is to identify strategies to optimally integrate immune therapy with current treatment regimens.
Methods: For these experiments, we used the syngeneic ID8ova murine model of high-grade serous ovarian cancer, which constitutively expresses ovalbumin. The in vitro effects of cisplatin on peritoneal T cells from tumor-bearing mice in culture were evaluated by flow cytometry. For in vivo experiments, mice received cisplatin (3mg/kg every 3 days x 4 doses) IV or IP starting on day 14 after tumor challenge. Peritoneal and peripheral T cells were harvested on day 1, 8, and 14 after treatment and used to analyze activation status, tumor specificity, and PD-1 immune checkpoint expression between IV and IP treated groups using flow cytometry.
Results: Exposing peritoneal lymphocytes to 100 μg/ml of cisplatin ex vivo enriched for CD8+ T cells with an effector and central memory phenotype [52.7% vs. 29.3% for untreated cells, p=0.001]. This was due to the disproportionate death of naïve cells, rather than phenotype switching. In vivo, we found that 15 days after treatment IP cisplatin increases the percent of effector CD8+ cells relative to IV cisplatin treatment [72.8% IP vs. 43.5% IV cisplatin (p=0.038)], and CD8+ cells expressing PD1 [45.80 % IP vs. 17.98% IV cisplatin (p=0.006)]. Changes in antigen-specific cells were trending, but not significant [38.29 % IP vs. 20.45% IV cisplatin, respectively (p=0.07)]. These changes were not seen in circulating lymphocytes.
Interpretation/Conclusions: Our results indicate that IP cisplatin enriches activated tumor-specific effector cells in the ovarian tumor environment. This effect is dose dependent and results from high local concentrations of cisplatin following IP administration. While the role of IP chemotherapy for ovarian cancer has come under scrutiny based on recent clinical trials, our data showing an increase in effector cells and expression of the inhibitory checkpoint receptor PD-1 suggest that IP cisplatin administration could positively prime the peritoneal tumor environment to enhance the efficacy of immune therapy in ovarian cancer.
Citation Format: Henning S. De May, Sharina Palencia Desai, Ichiko Kinjyo, Sarah F. Adams. Optimizing chemotherapy for the integration of immune therapy in ovarian cancer: Enriching effector T cells in the peritoneal tumor microenvironment using the route of cisplatin administration (IV vs. IP) [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B01.