Abstract 2685: Sensitizing mouse ovarian cancer tumors to immunotherapy

Abstract Introduction: The overall survival of patients with advanced ovarian cancer (OC) is poor and clinical responses to immunotherapy are low, encouraging development of new strategies that sensitize ovarian cancer to immunotherapy. Many studies in OC and other cancers have linked the presence of intra-tumoral B cells, high endothelial venules (HEVs) and lymphoid aggregates that resemble tertiary lymphoid structures (TLSs) with improved prognosis and increased survival. In contrast to the favorable prognosis associated with the presence of TLS, high levels of immunosuppressive T regulatory cells (Tregs) in OC are associated with reduced survival. Methods: Single, double, and triple combinations of a Treg depleting antibody, an HEV-inducing LTβR agonist antibody, and the anti-PD1 checkpoint inhibitor were tested in immune-competent C57Bl/6 mice inoculated intraperitoneally with homologous recombination defective (HRD) ID8 Trp53-/-Brca2-/- and HR proficient (HRP) ID8 Trp53-/- bioluminescent murine OC tumor models. Mono- and combination therapy was administered in fixed endpoint and survival studies and assessed for tumor burden, Treg depletion, HEV induction, lymphocyte infiltration, other changes to the tumor microenvironment, and overall survival. Results: High numbers of Tregs were found in control tumors which were significantly reduced in arms which included the Treg depleting antibody along with significantly increased numbers of CD8+ T cells. HEVs were significantly more abundant in arms which included the LTβR agonist along with increased numbers of B cells and plasma cells. Clonal selection of T cells occurred in treated tumors, most notably with triple combination treatment. In fixed endpoint trials, tumor burden was significantly reduced and sometimes completely eradicated in combination arms that included the Treg depleting antibody. Median survival in mice bearing ID8 Trp53-/-Brca2-/- tumors was increased in triple combination tumors vs IgG (130 vs 57 days) with 5/13 animals that completely eradicated tumors and successfully rejected tumor rechallenges. Analogous studies using ID8 Trp53-/- tumor cells produced 7/7 mice without a detectable bioluminescent tumor signal after 75 days (ongoing) while the IgG group had a median survival of 50 days. Conclusions: This study indicates that OC tumors in immune-competent mice can be sensitized to immunotherapy and potentially eradicated with checkpoint inhibition using a strategy that combines Treg depletion and/or HEV induction. Data generated in this study can provide the rationale for the design of a clinical trial in OC patients, possibly stratified by HR status, as a biomarker driven approach. Citation Format: Elizabeth Anne Allen, Justine Chen, Supreeti Tallapragada, Huyen Pham, Oliver Dorigo. Sensitizing mouse ovarian cancer tumors to immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2685.