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.
Author Info: (1) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (2) Department of Pa
Author Info: (1) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (2) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, 6550 Fannin Street, SM8026, Houston, TX, 77030, USA. (3) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (4) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (5) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (6) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (7) Department of Medicine, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA. (8) Department of Microbiology and Immunology and Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, 27599, USA. (9) Imaging core facility, Rutgers University-New Jersey Medical School, 205 South Orange Avenue, Newark, NJ, 07103, USA. (10) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (11) Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, 6550 Fannin Street, SM8026, Houston, TX, 77030, USA. (12) Department of Surgery, New Jersey Medical School, Rutgers-The State University of New Jersey, 185 South Orange Avenue, Newark, NJ, 07101, USA. (13) School of Pharmacy, Rutgers-The State University of New Jersey, Newark, 164 Frelinghuysen Road Piscataway, NJ, 08854, USA. (14) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. (15) Department of Pathology, Immunology and Laboratory Medicine, Rutgers University-New Jersey Medical School, 185 South Orange Avenue, Newark, NJ, 07103, USA. dongfang.liu@rutgers.edu. Center for Immunity and Inflammation, New Jersey Medical School, Rutgers-The State University of New Jersey, 185 South Orange Avenue, Newark, NJ, 07101, USA. dongfang.liu@rutgers.edu.
