Abstract 115: Developing uPAR CAR T Cells for High-Grade Serous Ovarian Cancer

Abstract

Abstract Chimeric Antigen Receptor (CAR) T cells are a modality of immunotherapy that act to eliminate cancer cells by redirecting the cytolytic activity through targeting a protein overexpressed on the surface of the cancer cell. In contrast to move conventional cancer therapies, their anti-cancer activity does not depend on a cancer-specific molecular vulnerability but rather the differential expression of the target antigen on tumor cells compared to normal tissues. We have developed CAR T cells targeting the urokinase plasminogen activator receptor (uPAR), which is overexpressed on senescent cells but not expressed highly in vital organs, to selectively target senescent cells in a range of tissue damage pathologies where they are known to be pathogenic. uPAR is also highly overexpressed in a wide range of cancer types, including pancreatic, kidney, bladder, brain and ovarian carcinomas, respectively, raising the possibility that CAR T cells targeting uPAR may also be effective against cancer. Indeed, leveraging an electroporation-based genetically-engineered mouse model of ovarian cancer, we demonstrate the robust anti-tumor efficacy of murine uPAR CAR T cells in immunocompetent syngeneic mice. Moreover, through an exhaustive functional screening of 37 distinct human uPAR single-chain fragment variants (scFVs), we have successfully identified lead scFVs exhibiting subnanomolar affinity to membrane-anchored uPAR. Significantly, these human uPAR CAR T cells exhibit the capability to eliminate both orthotopic and metastatic human HGSOC xenograft tumors without inducing severe adverse effects. Ongoing efforts encompass the assessment of the long-term safety and toxicity profiles of uPAR CAR T cells utilizing a humanized mouse model platform. Our results provide a strong rationale for developing uPAR CAR T cells as an anticancer strategy relevant to a broad range of tumor types, and provide an avenue for safety profiling of uPAR CAR T cells prior to clinical testing in non-cancer patients harboring senescence-related pathologies. Citation Format: Zeda Zhang, Xin Fang, Yu-jui Ho, Sascha Haubner, Friederike Kogel, Clemens Hinterleitner, Stella Paffenholz, Kevin Chen, Wei Luan, Amanda Kulick, Gertrude Gunset, Andreina Garcia Angus, Jing Zhang, Zijian Xu, Adam Wang, Qingwen Jiang, Elisa de Stanchina, Britta Weigelt, Dmitriy Zamarin, Aveline Filliol, Judith Feucht, Jorge Mansilla-Soto, Corina Amor, Michel Sadelain, Scott Lowe. Developing uPAR CAR T Cells for High-Grade Serous Ovarian Cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 115.