Li Kesang, Qian Suying, Huang Mengmeng, Chen Mengjie, Peng Ling, Liu Jianwen, Xu Wen, Xu Jianfen
Department of Hematology and Oncology, Hwa Mei Hospital, University of Chinese Academy of Sciences Ningbo 315000, Zhejiang, China.
Ningbo Institute of Life and Health Industry, University of Chinese Academy of Sciences Ningbo 315000, Zhejiang, China.
Am J Transl Res. 2021 Jan 15;13(1):156-167. eCollection 2021.
Adoptive transfer of T cells expressing specific anti-glypican-3 (GPC3) chimeric antigen receptors (CARs) has demonstrated therapeutic potential against hepatocellular carcinoma (HCC). However, normal tissues with low expression of neoplasm-associated antigens often show on-target, off-tumor toxicity. Previous studies have revealed that the development of HCC xenografts in mice could be inhibited effectively by GPC3-targeting CAR-T cells. However, these studies did not provide information regarding on-target, off-tumor toxicity. We hypothesized that on-target, off-tumor toxicity may decrease in dual-targeting CAR-T cells that co-express GPC3 with epidermal growth factor receptor (EGFR)-targeted CARs characterized by CD3ζ and 28BB expression. Our research confirmed that dual-targeting CAR-T (CARgpc3-egfr) cells exhibited similar proliferative ability and cytotoxicity to CARgpc3 T cells against GPC3+EGFR+ HCC . However, EGFR-targeting CAR-T (CARegfr) cells showed poor proliferation activity and cytotoxicity against GPC3+EGFR+ HCC cells, similar to mock CAR-T cells. CARgpc3 and CARgpc3-egfr T cells showed enhanced cytokine secretion compared to CARegfr and mock CAR-T cells . , tumor growth suppression was better for CARgpc3-egfr T cells than for CARgpc3 T cells in GPC3+EGFR+ HCC, while it was not observed for CARegfr or mock CAR-T cells. Taken together, our data indicated that dual-targeting CAR-T cells with two CARs against GPC3 and EGFR may maintain relatively effective anti-neoplasm functions in GPC3+EGFR+ HCC and , a strategy that may reduce off-tumor toxicity.
表达特异性抗磷脂酰肌醇蛋白聚糖-3（GPC3）嵌合抗原受体（CAR）的T细胞的过继性转移已显示出对肝细胞癌（HCC）的治疗潜力。然而，肿瘤相关抗原低表达的正常组织常表现出靶向非肿瘤毒性。先前的研究表明，靶向GPC3的CAR-T细胞可有效抑制小鼠肝癌异种移植瘤的生长。然而，这些研究并未提供有关靶向非肿瘤毒性的信息。我们推测，共表达GPC3与以CD3ζ和28BB表达为特征的表皮生长因子受体（EGFR）靶向CAR的双靶向CAR-T细胞中，靶向非肿瘤毒性可能会降低。我们的研究证实，双靶向CAR-T（CARgpc3-egfr）细胞对GPC3+EGFR+HCC表现出与CARgpc3 T细胞相似的增殖能力和细胞毒性。然而，靶向EGFR的CAR-T（CARegfr）细胞对GPC3+EGFR+HCC细胞的增殖活性和细胞毒性较差，类似于模拟CAR-T细胞。与CARegfr和模拟CAR-T细胞相比，CARgpc3和CARgpc3-egfr T细胞显示出增强的细胞因子分泌。在GPC3+EGFR+HCC中，CARgpc3-egfr T细胞对肿瘤生长的抑制作用优于CARgpc3 T细胞，而CARegfr或模拟CAR-T细胞则未观察到这种抑制作用。综上所述，我们的数据表明，针对GPC3和EGFR的双靶向CAR-T细胞可能在GPC3+EGFR+HCC中维持相对有效的抗肿瘤功能，并且这可能是一种降低非肿瘤毒性的策略。
