Abstract POSTER-THER-1434: Intraperitoneal anti-PD-L1 increases survival in a novel ovarian cancer model and its in vivo efficacy is influenced by baseline anti-tumor immunity of the host
Authors: Mony Jyothi , Zhang Lixin , Tirodkar Tejas , Elishaev Esther , Brozick Joan , Edwards Robert P. , Vlad Anda M. 
Published: August 2015

Purpose: Immunotherapy with monoclonal antibodies that block inhibitory immune checkpoint molecules and enhance antitumor responses has recently showed clinical promise in advanced solid tumors. However, most of the preliminary evidence on therapeutic efficacy comes from melanoma, prostate and lung cancer. Further studies on other tumor types (including ovarian cancer), and on additional, potentially more effective regimens that take into consideration the administration route and baseline immune status of the host, are currently needed.

Approach: We recently generated a triple transgenic MUC1+/-KrasG12D/+PtenloxP/loxP (MKP) mouse model that carries a conditional, oncogenic Kras mutation, Pten deletion and express human MUC1 as self. Upon AdCre injection under the ovarian bursa, the MKP mice progress to endometrioid ovarian tumors that overexpress MUC1 tumor-associated antigen. Using an orthotopic MKP ovarian tumor, we generated a new ovarian cancer cell line (2F8). MUC1.Tg mice injected IP with 8x10E5 of completely syngeneic 2F8 cells develop IP tumors. Mice wild-type for MUC1 were similarly challenged with 2F8 cells, thus creating an isogenic system, in which the hosts are syngeneic to all other tumor antigens, except for human MUC1.

Results: At baseline, the cells express low PD-L1 but expression increases after in vivo growth. Anti-PDL1 was administered IP every 2 weeks (200 mg/dose) for a total of 3 doses. Treatment was started 21 days post-tumor challenge, a time point which corresponds to a late tumor stage.

The anti-PD-L1 treated MUC1.Tg mice showed substantial T cell infiltration within the tumor and significantly increased survival (p= 0.001) compared to isotype control- treated mice. In contrast, wild type mice with isogenic 2F8 tumors developed spontaneous, high titer anti-MUC1 antibodies and did not respond to anti-PD-L1 therapy. However, earlier treatment (at day 11, instead of day 21) post tumor challenge, higher frequency of IP injections (weekly) and higher overall dose (seven doses, 200 μg/dose) increased treatment efficacy in these mice and led to increased survival. Anti-PDL1 therapy did not change the amplitude of MUC1 specific antibodies in responding mice. In addition to the above quantitative and qualitative changes in systemic and intratumoral T cells, broad range profiling using microarrays are ongoing and will reveal the hallmarks of response in anti-PD-L1 treated mice.

Conclusions: These results demonstrate that targeting PD-L1 is a viable therapeutic strategy in ovarian cancer and can increases survival despite (1) treatment initiation at late stage, (2) low dose/low frequency of administration and (3) low PD-L1 expression on tumors. By employing an isogenic animal model that favors anti-tumor humoral immunity, we show here that tumor-bearing hosts with antibody-driven immune imbalance at time of treatment initiation are non-responsive and may require a more dose intensive regimen. This is in line with our previous findings showing inverse correlation between survival and pre-existing MUC-1 specific antibody levels in ovarian cancer patients receiving IP Interleukin -2 (IL-2). Our studies have high translational potential and support IP administration of PD-L1 blockers in ovarian cancer patients, while taking into consideration pre-existent, anti-tumor antibodies.

Citation Format: Jyothi Mony, Lixin Zhang, Tejas Tirodkar, Esther Elishaev, Joan Brozick, Robert P. Edwards, Anda M. Vlad. Intraperitoneal anti-PD-L1 increases survival in a novel ovarian cancer model and its in vivo efficacy is influenced by baseline anti-tumor immunity of the host [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-THER-1434.