Abstract LB092: Identification of target antigens for logic-gated CAR-T therapeutics for the treatment of clear cell renal cell carcinoma: conditional targeting of CA9 with a PSMA PrimeR

Abstract

Abstract Chimeric antigen receptor T (CAR T) cell therapeutics have produced curative outcomes in hematological malignancies but have yet to be developed into safe and effective therapies for solid tumors. A major obstacle to developing targeted therapies against solid malignancies is the identification of targets that are abundantly and broadly expressed on tumor cells while exhibiting an absence of expression on high toxicity risk normal tissues. Logic-gated CAR T cells that inducibly express CAR upon recognition of a target antigen by a secondary engineered priming receptor (PrimeR) offer a novel approach to permit conditional killing activity in the presence of two antigens. Here, we identify PSMA and CA9 as attractive priming and cytolytic antigen targets, respectively, in clear cell renal cell carcinoma (ccRCC). Using a bioinformatic discovery path, we show PSMA and CA9 mRNA are co-expressed in 94% of ccRCC tumors (n=530, TCGA). Immunohistochemical (IHC) assessments further reveal robust membranous PSMA and CA9 protein coexpression in 80% of ccRCC (n=416). Expression of CA9 and PSMA was evaluated across disease stage and co-expression was confirmed throughout disease progression. Distant metastases similarly showed evidence of common expression. In contrast, IHC assessment of normal tissues revealed limited membranous coexpression of PSMA and CA9 in normal high-risk toxicity tissues. These findings collectively support the utility of PSMA and CA9 as target antigens for AND-logic-gated therapeutics for the treatment of ccRCC. Citation Format: Nickolas Attanasio, Levi Gray-Rupp, Stanley Zhou, Samuel A. Williams. Identification of target antigens for logic-gated CAR-T therapeutics for the treatment of clear cell renal cell carcinoma: conditional targeting of CA9 with a PSMA PrimeR [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB092.