Abstract IA012: Mechanisms and consequences of bispecific T-cell engager immunotherapy for ovarian cancer

Abstract There have been several important advancements in the management of ovarian cancer. Antibody drug conjugates have been transformative for this disease, but knowledge on the mechanisms of resistance to this modality and potential therapeutic salvage options are limited. Emerging data suggest that antigen loss or downregulation may not be a major contributor to resistance to antibody drug conjugates. Bispecific T-cell Engagers have the potential to exploit the persistent antigen expression in antibody drug conjugate-resistant ovarian cancer by binding these targets and redirecting polyclonal T-cells to facilitate cytotoxicity. Bispecific T-cell engagers have been approved for the treatment of uveal melanoma, but testing in other solid tumors, such as ovarian cancer, is ongoing. We identified the tumor-retained portion of the cancer antigen Muc16/CA125, MUC16-ectodomian (Muc16ecto), as a suitable target for bispecific T-cell engager therapy. We developed antibodies against Muc16ecto and showed that bispecific T-cell engagers lead to cytotoxicity against ovarian cancer cells in vitro and in vivo. Even in the presence of shed CA125, bispecific engagers against Muc16ecto preferentially bound to the intended cell-retained target. Furthermore, we found that the efficacy of Muc16ecto bispecific engagers was increased when combined with either anti-PD1 antibodies or anti-VEGF antibodies, the latter providing greater efficacy. Bispecific engagers for ovarian cancer, including one targeting Muc16ecto, are undergoing evaluation in clinical trials. We collected samples from patients experiencing progression of disease on these bispecific engagers to understand mechanisms of resistance. We found Muc16ecto downregulation in tumor samples obtained from patients experiencing progression on Muc16ecto-directed bispecific engagers. Our data showed that the relatively hypoxic peritoneal tumor microenvironment drove this process. Peripheral T-cells from patients experiencing progression were still capable of cytotoxicity against cancer cells ex vivo in the presence of tumors with retained Muc16ecto expression. Serum from these patients suppressed cytotoxicity, suggesting that other factors besides antigen downregulation were involved. We found that downregulation of Muc16ecto led to an epithelial to mesenchymal transition of ovarian cancer cells and increased VEGF secretion. Soluble VEGF alone was enough to blunt Muc16ecto bispecific T-cell activity, and this was found to be due to decreased T-cell proliferation and increased T-cell apoptotic priming. Our data posit that tumor heterogeneity due to VEGF secretion from hypoxic progressing sites, leading to disease progression at other non-hypoxic metastatic sites, could be a significant contributor to therapeutic failure. Citation Format: Oladapo Yeku, Mengyao Xu, Syem K. Barakzai, Raj Kumar, Irva Veillard. Mechanisms and consequences of bispecific T-cell engager immunotherapy for ovarian cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Ovarian Cancer Research; 2025 Sep 19-21; Denver, CO. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl):Abstract nr IA012.