Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma
Tseng Hsiang-Chi, Wei Xiong, Saiaditya Badeti, Yan Yang, Minh Ma, Ting Liu, Carlos A. Ramos, Gianpietro Dotti, Luke Fritzky, Jie-gen Jiang, Qing Yi, James V. Guarrera, Wei‐Xing Zong, Chen Liu, Dongfang Liu
Abstract
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.