Abstract B037: AB-2100, a PSMA-inducible CA9-specific CAR T cell product intended for the treatment of ccRCC provides long-term tumor responses in preclinical mouse model
Authors: Mohanty Suchismita , Chen Jeremy , Gomez Alma , Boroughs Angela , Scarfo Irene , Lim Laura , Dang Kevin , Chew Marvin , Sudhakar Rakesh , Nguyen Michelle , Gardner Thomas , Millare Beatriz , Zhang James , Moskowitz Darrian , Zhou Stanley , Xie Neroli H. , Attanasio Nickolas , Fearon Amanda , Chan Ivan , Sail Vibhavari , Thomas Vince , Smith Jennesa , McDevitt Jennifer , Gray-Rupp Levi , Gonzalez Alba , Murriel Christopher , Haining W. Nicholas 
Published: October 2024

Common challenges of CAR-T cell therapies in solid tumors, such as clear cell renal cell carcinoma (ccRCC), include insufficient therapeutic potency and tumor specificity. AB-2100 is an autologous integrated circuit T cell product generated via CRISPR-mediated knock-in of a single transgene into a safe-harbor locus. AB-2100 encodes a transcriptionally regulated sequential AND gate that comprises a priming receptor (PrimeR) specific for PSMA and an inducible CAR targeting CA9 antigen, which is widely expressed on ccRCC tumor cells. AB-2100’s sequential AND logic-gate design aims to confer tumor-specific activity by priming off of PSMA-expressing tumor vasculature to induce CA9 CAR expression. The logic gate is intended to increase the safety profile of AB-2100 given that PSMA and CA9 are predicted to have limited co-expression in normal tissues. Additional enhancements in T cell functionality include short-hairpin RNAs (shRNA) against Fas and TGFBR2 designed to prevent tumor microenvironment (TME)-mediated suppression, and a synthetic pathway activator (SPA) designed to drive constitutive STAT3 signaling and to enhance T cell expansion and antitumor activityMechanism of action studies demonstrate that AB-2100 can prime off of PSMA-expressing endothelial cells and induce tumor-specific killing of CA9 tumor cells, leading to the eradication of ccRCC targets in vitro. AB-2100 also exhibited selective killing of dual antigen expressing tumors in vivo using a dual-flank subcutaneous xenograft model. Evaluation of AB-2100 in the subcutaneous A498 xenograft model demonstrated that inclusion of the SPA resulted in significant increase in antitumor efficacy. Furthermore, a rechallenge xenograft model demonstrated that presence of SPA increased the long term functional persistence of AB-2100. In summary, preclinical data demonstrate that AB-2100 selectively targets tumors co-expressing PSMA and CA9, and can overcome multiple suppressive mechanisms in the tumor microenvironment. These results support the ongoing evaluation of AB-2100 for the treatment of advanced or metastatic ccRCC.

Citation Format: Suchismita Mohanty, Jeremy Chen, Alma Gomez, Angela Boroughs, Irene Scarfo, Laura Lim, Kevin Dang, Marvin Chew, Rakesh Sudhakar, Michelle Nguyen, Thomas Gardner, Beatriz Millare, James Zhang, Darrian Moskowitz, Stanley Zhou, Neroli H. Xie, Nickolas Attanasio, Amanda Fearon, Ivan Chan, Vibhavari Sail, Vince Thomas, Jennesa Smith, Jennifer McDevitt, Levi Gray-Rupp, Alba Gonzalez, Christopher Murriel, W. Nicholas Haining. AB-2100, a PSMA-inducible CA9-specific CAR T cell product intended for the treatment of ccRCC provides long-term tumor responses in preclinical mouse model [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr B037.