Medical School of Fudan University, Shanghai, China. State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Clin Cancer Res. 2014 Dec 15;20(24):6418-28. doi: 10.1158/1078-0432.CCR-14-1170. Epub 2014 Oct 15.
The aim of our study is to elucidate whether T cells expressing GPC3-targeted chimeric antigen receptor (CAR) can efficiently eliminate GPC3-positive HCC cells and their potential in the treatment of HCC.
T cells expressing a first-generation and third-generation GPC3-targeted CAR were prepared using lentiviral vector transduction. The in vitro and in vivo cytotoxic activities of the genetically engineered CAR T cells were evaluated against various HCC cell lines.
GPC3-targeted CAR T cells could efficiently kill GPC3-positive HCC cells but not GPC3-negative cells in vitro. These cytotoxic activities seemed to be positively correlated with GPC3 expression levels in the target cells. In addition, T cells expressing the third-generation GPC3-targeted CAR could eradicate HCC xenografts with high level of GPC3 expression and efficiently suppress the growth of HCC xenografts with low GPC3 expression level in vivo. The survival of the mice bearing established orthotopic Huh-7 xenografts was significantly prolonged by the treatment with the third-generation GPC3-targeted CAR T cells.
GPC3-targeted CAR T cells could potently eliminate GPC3-positive HCC cells, thereby providing a promising therapeutic intervention for GPC3-positive HCC.
本研究旨在阐明表达 GPC3 靶向嵌合抗原受体（CAR）的 T 细胞是否能有效清除 GPC3 阳性 HCC 细胞，并探讨其在 HCC 治疗中的潜力。
利用慢病毒载体转导技术制备表达第一代和第三代 GPC3 靶向 CAR 的 T 细胞。评估基因工程 CAR T 细胞对各种 HCC 细胞系的体外和体内细胞毒性作用。
GPC3 靶向 CAR T 细胞可有效杀伤体外的 GPC3 阳性 HCC 细胞，但不能杀伤 GPC3 阴性细胞。这些细胞毒性作用似乎与靶细胞中 GPC3 的表达水平呈正相关。此外，表达第三代 GPC3 靶向 CAR 的 T 细胞可清除高表达 GPC3 的 HCC 异种移植瘤，并在体内有效抑制低表达 GPC3 的 HCC 异种移植瘤的生长。第三代 GPC3 靶向 CAR T 细胞治疗可显著延长携带已建立的原位 Huh-7 异种移植瘤小鼠的存活时间。
GPC3 靶向 CAR T 细胞可有效清除 GPC3 阳性 HCC 细胞，为 GPC3 阳性 HCC 提供了一种有前景的治疗干预手段。
