Abstract 1117: Investigating PD-1/PD-L1 checkpoint inhibition as a treatment for platinum-resistant ovarian cancer

Abstract

Abstract Ovarian cancer is the deadliest cancer of the female reproductive system, with the majority of patients experiencing relapse on first-line platinum-based chemotherapies. Identifying potential targets for additional second-line therapies is critical for treating platinum-resistant ovarian cancer. To that end, the evolution of platinum resistance in a cell-based model of ovarian cancer was monitored via characterization of proteomic changes in cancer-derived extracellular vesicles (EVs) after progressive rounds of cisplatin treatment. The content of cancer-derived EVs was analyzed via reverse phase protein array, mass spectrometry, and Western blotting to identify pathways that could be targeted by second-line therapies. Several therapeutically relevant markers were upregulated, including phospho-EGFR (Y1068), multidrug transporter ABCE1, and PD-L1. Monoclonal antibody-based therapies (mAbs) targeting PD-1/PD-L1 have been deployed successfully as second-line treatments for a variety of cancers, but their success has yet to be translated to ovarian cancer. Current mAb-based immunotherapies suffer from several pitfalls including poor tissue penetration, a long-standing issue in ovarian cancer treatment. To offer an alternative to mAb-based immunotherapies, we developed a small interfering peptide consisting of a portion of the PD-L1 interface sequence. This lead peptide underwent several rounds of in silico optimization via molecular dynamics and modeling simulations to identify modifications that could improve affinity for PD-1 or stability in serum. When efficacy was assessed in vitro via Amplified Luminescent Proximity Homogeneous Assay screening, the modifications to the lead peptide were not shown to improve efficacy. However, serum stability studies indicated the modifications dramatically improved peptide stability, with detectable levels still quantifiable via mass spectrometry after 48 hours. The stabilized peptide, titled MN1.4, was chosen for further efficacy testing in cell-based models. A cisplatin-treated daughter line from the OVCAR8 high grade serous ovarian carcinoma cell line was created to model the effects of clinical platinum-based chemotherapy treatments on the most common ovarian cancer subtype. OVCAR8 cells were co-cultured in the presence of stimulated Jurkat T cells to measure markers of T cell activation, including IL-2, via ELISA after treatment with MN1.4 in the presence or absence of EVs derived from cisplatin-treated cells. This model allows for examination of the potential sensitization effects of first-line cisplatin treatment on PD-1/PD-L1 immunotherapy, and how cancer-derived EVs from cisplatin-treated cells can abrogate this effect. We conclude that exosomal PD-L1 may impair responses to PD-1/PD-L1 immunotherapy and should be considered when assessing the viability of this treatment option for ovarian cancer patients. Citation Format: Rachel Carter, Marissa Howard, James Erickson, Paul Russo, Alessandra Luchini, Amanda Haymond, Fatah Kashanchi, Mikell Paige, Lance Liotta. Investigating PD-1/PD-L1 checkpoint inhibition as a treatment for platinum-resistant ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1117.