Abstract 260: In vivo efficacy of intraperitoneal anti-PD-L1 therapy in ovarian cancer
Authors: Shannon Grabosch, Jyothi T. Mony, Lixin Zhang, Tianzhou Ma, Tejas Tirodkar, Joan Brozick, George Tseng, Esther Elishaev, Robert P. Edwards, Xin Huang, Anda M. Vlad
Journal: Cancer Research (2015)

Abstract Objectives: Programmed cell death ligand 1 (PD-L1) is an immune checkpoint cell surface molecule expressed on many types of cancers including ovarian cancer. Its interaction with the programmed death (PD-1) receptor on T cells essentially halts the immune response and allows tumor escape. Monoclonal antibodies to either PD-L1 or PD-1 block this interaction and show efficacy in a variety of cancers, though to a lesser degree in ovarian cancer. We have evaluated the efficacy of intraperitoneal anti-PD-L1 therapy in two ovarian cancer mouse models. Methods: Murine 2F8 tumor cells derived from an orthotopic tumor isolated from a triple transgenic MUC1+/−KrasG12D/+PtenloxP/loxP (MKP) mouse as we recently described. MUC1 transgenic (MUC1.Tg) mice received an intraperitoneal inoculation of 8×105 syngeneic 2F8 cells. Untreated mice develop extensive tumor burden and expire around 29 days. Mice were treated with 200 μg anti-PD-L1 antibody (or rat IgG as control) every two weeks for three doses starting at 21 days post-inoculation, thus corresponding with late tumor stage. C57BL/6 mice were inoculated via intraperitoneal (IP) injection with 1×106 IG10 (spontaneously transformed mouse ovarian surface epithelial) tumor cells. Treatment with anti-PD-L1 (or rat IgG as control) started 22 days following inoculation when the mice began showing ascites. Immunohistochemistry for perforin was performed on tumor tissue sections. Immune gene profiling of spleen cells collected at necropsy was performed via Nanostring, using 561 mouse immunology-related genes. Results: The 2F8 tumors are aggressive with little T cell infiltration. The anti-PD-L1 treated MUC1.Tg mice showed substantial infiltration of perforin positive cells within the tumor and significantly increased survival (p = 0.001) compared to isotype control- treated mice. Splenocyte profiling of 561 immune genes via Nanostring revealed a treatment-induced immune gene signature that points to T cell functions and cytotoxic anti-tumor immune responses. A similar gene signature favoring cytotoxic anti-tumor activity was also revealed in IG10 tumor bearing C57Bl/6 mice treated with anti-PD-L1. Conclusion: These preclinical results from two different ovarian cancer tumor models demonstrate that targeting PD-L1 is a viable therapeutic strategy in ovarian cancer and increases survival despite (1) non-immunogenic tumors, (2) late treatment initiation, (3) low dose and administration frequency. The tumors respond well to anti-PD-L1 blockade, due to increased systemic T cell responses and intratumoral T cell accumulation, without changing tumor-specific antibody levels. Our studies have high translational potential and support IP administration of PD-L1 blockers in ovarian cancer patients. Citation Format: Shannon Grabosch, Jyothi T. Mony, Lixin Zhang, Tianzhou Ma, Tejas Tirodkar, Joan Brozick, George Tseng, Esther Elishaev, Robert P. Edwards, Xin Huang, Anda M. Vlad. In vivo efficacy of intraperitoneal anti-PD-L1 therapy in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 260. doi:10.1158/1538-7445.AM2015-260