Using A Psma-Specific Low-Molecular-Weight Compound For Prostate Cancer Treatment With Rapidly Switchable Universal Car-T Cells: Overcoming The Challenges Of Cellular Immunotherapies In Solid Tumors

CAR-T cell therapy holds great promise for treating a wide range of malignancies. Nevertheless, the CAR-T approach faces multiple challenges, including lack of suitable targets, insufficient tumor penetration and a microenvironment hostile to CAR-T cells. Here we provide pre-clinical evidence for using a low-molecular-weight, chemically synthesized compound to re-target CAR-T cells against solid tumors in conjunction with the CD28 co-stimulatory domain to address several of these challenges. PSMA is a validated target for treatment of advanced and metastatic prostate cancer (PCa), but also broadly expressed on tumor neo-vasculature beyond PCa. PSMA is also known to be expressed on a number of normal tissues, albeit to a much lower extent, which necessitates additional safety mechanisms for CAR-T therapy. Therefore, a rapidly switchable universal CAR-T platform (UniCAR) was developed. In this system, antigen-specificity is provided by soluble adaptors termed targeting modules (TM), which redirect T-cells engineered to express a universal CAR in an antigen-specific manner against tumors. The TM explored in the present study incorporates a clinically well-characterized radiotracer peptide motif binding to the enzymatic groove of PSMA. The small-sized TM has favorable pharmacokinetic and pharmacodynamics properties (short half-life of Citation Format: Marc Cartellieri, Simon Loff, Johannes Spehr, Mridula Swayampakula, Julia Riewaldt, Cordula Grunder, Maria Schreiber, Michael Bachmann, Anja Feldmann, Michael Pehl, Gerhard Ehninger, Armin Ehninger. Using a PSMA-specific low-molecular-weight compound for prostate cancer treatment with rapidly switchable universal CAR-T cells: Overcoming the challenges of cellular immunotherapies in solid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2176.