Abstract 3189: Pre-clinical evaluation of novel folate receptor 1 directed CAR T cells for high grade serous ovarian cancer

Abstract

Abstract Purpose: Treatment of ovarian cancer remains challenging. A high unmet clinical need for targeted, efficient, and persisting drugs still is a major issue for clinicians and patients diagnosed with ovarian cancer, particularly platinum-resistant and-refractory, recurrent disease. Genetically modified T cells expressing chimeric antigen receptors (CARs) have shown efficient, as well as persisting anti-tumor functionality in hematological malignancies. However, solid cancers have not yet been as efficiently treated with CAR T cells, potentially due to the lack of appropriate targets. Therefore, we thoroughly characterized FOLR1 as CAR T cell target for ovarian cancer, designed novel CAR T cells, and assessed these drug candidates preclinically in vitro and in vivo. Experimental Design: We performed ultra-high content imaging on high-grade serous epithelial ovarian cancer as well as healthy tissue samples to profile the expression of the tumor-associated antigen FOLR1. Subsequently, we designed a series of CAR T cell candidates based on different monoclonal antibodies targeting FOLR1, in order to leverage on clinical experience with these binders, particularly safety aspects. The CAR designs differed in the VL-VH orientation and the spacer domain of the CAR construct. The preclinical assessment of various FOLR1-directed CAR T cell constructs was evaluated against various ovarian cancer cell lines in vitro and in vivo. Results: In this study we show high and consistent expression of the tumor-associated antigen FOLR1 on primary ovarian cancer samples, namely high-grade serous ovarian cancer. Moreover, FOLR1 expression is low, restricted, and polarized in healthy tissues. We generated diverse FOLR1-specific CAR T cells and characterized their efficacy and specificity in vitro as well as in an ovarian cancer xenograft model. CAR T cells rapidly and efficiently eradicate xenograft tumors. This anti-tumor response is accompanied by CAR T cell expansion, FOLR1-dependent cytokine secretion, and infiltration of CAR T cells into the tumor. Conclusions: These findings demonstrate the feasibility of a preclinical CAR T cell approach targeting FOLR1 as treatment option for ovarian cancer and potentially other FOLR1-expressing tumors. Citation Format: Christoph Herbel, Julie Daigre, Manuel Martinez-Osuna, Maria Bethke, Larissa Steiner, Janina Brauner, Jens Kopatz, Paurush Praveen, Dominik Eckardt, Andreas Bosio. Pre-clinical evaluation of novel folate receptor 1 directed CAR T cells for high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3189.