Efficacy of anti-CD147 chimeric antigen receptors targeting hepatocellular carcinoma

• DOI: 10.1038/s41467-020-18444-2
• Publication Date: 2020-09-23T10:03:33Z
• Authors: Hsiang-chi Tseng; Wei Xiong; Saiaditya Badeti; Yan Yang; Minh Ma; Ting Liu; Carlos A. Ramos; Gianpietro Dotti; Luke Fritzky; Jie-gen Jiang; Qing Yi; James Guarrera; Wei-Xing Zong; Chen Liu; Dongfang Liu
• Keywords: Male; Mice, Knockout; 0301 basic medicine; Carcinoma, Hepatocellular; Receptors, Chimeric Antigen; Science; Q; Liver Neoplasms; Mice, Transgenic; Hep G2 Cells; Immunotherapy, Adoptive; Xenograft Model Antitumor Assays; Article; 3. Good health; Killer Cells, Natural; Disease Models, Animal; Mice; 03 medical and health sciences; Liver; Cell Line, Tumor; Basigin; Animals; Humans; Female

AbstractChimeric 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.