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.
Nat Commun. 2020 Sep 23;11(1):4810. doi: 10.1038/s41467-020-18444-2.
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 (GPC3CD147), but not single antigen (GPC3CD147) 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.
嵌合抗原受体 (CAR) 疗法是治疗多种难治性血液癌症的一种有前途的免疫治疗策略，但实体瘤 CAR 疗法还需要进一步的进展。一个挑战是确定安全有效的肿瘤抗原。在这里，我们设计了一种针对肝细胞癌 (HCC，最致命的恶性肿瘤之一) 的策略。我们报告说，转导了识别表面标记物 CD147（也称为 Basigin）的 CAR 的 T 和 NK 细胞可以有效地在体外杀死各种恶性 HCC 细胞系，并在异种移植和患者来源的异种移植小鼠模型中杀死 HCC 肿瘤。为了最大限度地减少任何靶内/靶外毒性，我们使用逻辑门控 (log) GPC3-synNotch 诱导的 CD147-CAR 来靶向 HCC。logCD147-CAR 选择性地杀死双重抗原 (GPC3CD147)，而不是单抗原 (GPC3CD147) 阳性 HCC 细胞，并且在人 CD147 转基因小鼠模型中不会引起严重的靶内/靶外毒性。总之，这些发现支持了 CD147-CAR 修饰的免疫细胞治疗 HCC 患者的治疗潜力。
