Definition

A preparation of autologous T lymphocytes that have been modified to encode a genetic circuit consisting of a priming receptor that induces the expression of a chimeric antigen receptor (CAR) specific for the tumor-associated antigen (TAA) carbonic anhydrase IX (CAIX; carbonic anhydrase 9; CA9; G250) upon binding to the TAA prostate-specific membrane antigen (PSMA), and a microRNA-adapted short hairpin RNA (shRNA-miR) module targeting Fas (FAS; CD95; APO-1; tumor necrosis factor receptor superfamily member 6; TNFRSF6) and human transforming growth factor beta (TGF-beta) receptor II (TGFbRII; TGFBR2), with potential immunomodulating and antineoplastic activities. Upon administration, autologous PSMA-inducible anti-CA9 CAR T cells AB-2100 target and bind to PSMA expressed on tumor cells and in tumor-associated neovasculature, and induce the expression of anti-CA9 CAR, thereby killing PSMA- and CA9-expressing tumor cells. The downregulation of the expression of Fas by the shRNA-miR prevents Fas-mediated apoptosis of the AB-2100 T-cells in the tumor microenvironment (TME). The downregulation of the expression of TGFbRII abrogates TGF-beta-mediated immunosuppression in the TME. PSMA is expressed on the membrane of prostatic epithelial cells and overexpressed on prostate tumor cells as well as in a variety of other tumors, including renal cell carcinomas. CA9 is a member of the carbonic anhydrase family that is found in a majority of renal cell carcinomas while absent in most normal tissues. AB-2100 T cells have also been engineered to include a constitutive synthetic pathway activator that increases signal transducer and activator of transcription 3 (STAT3) signaling, thereby promoting T-cell cytotoxicity and expansion.