Tseng, Xiong, Badeti, and Yang et al. showed that lower patient survival correlates with tumor expression of CD147, and that primary hepatocellular carcinomas (HCC) express CD147. CD147-CAR-transduced NK-92MI, primary NK, or T cells specifically lysed CD147+ HCC cell lines in vitro and slowed cell line growth in vivo. CAR-NK-92MI controlled patient-derived liver cancer xenografts. CD147-CAR-transduced primary NK cells from HCC livers lysed CD147+ HCC cell lines. Co-transduction of CD147-CAR cells with a synNOTCH inducible glypican-3 (GPC3)-specific CAR licensed selective killing/control of dual-antigen GPC3+CD147+ HCC cells in vitro and in vivo.
Contributed by Paula Hochman
ABSTRACT: Chimeric antigen receptor (CAR) therapy is a promising immunotherapeutic strategy for treating multiple refractory blood cancers, but further advances are required for solid tumor CAR therapy. One challenge is identifying a safe and effective tumor antigen. Here, we devise a strategy for targeting hepatocellular carcinoma (HCC, one of the deadliest malignancies). We report that T and NK cells transduced with a CAR that recognizes the surface marker, CD147, also known as Basigin, can effectively kill various malignant HCC cell lines in vitro, and HCC tumors in xenograft and patient-derived xenograft mouse models. To minimize any on-target/off-tumor toxicity, we use logic-gated (log) GPC3-synNotch-inducible CD147-CAR to target HCC. LogCD147-CAR selectively kills dual antigen (GPC3(+)CD147(+)), but not single antigen (GPC3(-)CD147(+)) positive HCC cells and does not cause severe on-target/off-tumor toxicity in a human CD147 transgenic mouse model. In conclusion, these findings support the therapeutic potential of CD147-CAR-modified immune cells for HCC patients.