Bispecific GPC3/PD-1 CAR-T cells for the treatment of HCC

被引:26
作者
Li, Dezhi [1 ]
Qin, Jie [2 ]
Zhou, Tao [1 ]
Li, Yaqin [3 ]
Cheng, Xianyi [1 ]
Chen, Zaizhong [1 ]
Chen, Junhui [1 ]
Zheng, Wei V. [1 ]
机构
[1] Peking Univ Shenzhen Hosp, Intervent & Cell Therapy Ctr, 1120 Lianhua Rd, Shenzhen 518036, Guangdong, Peoples R China
[2] Peking Univ Shenzhen Hosp, Dept Sci & Res, Shenzhen 518036, Guangdong, Peoples R China
[3] Peking Univ Shenzhen Hosp, Dept Infect Dis, Shenzhen 518036, Guangdong, Peoples R China
关键词
glypican-3; programmed death 1; chimeric antigen receptor; hepatocellular carcinoma; cancer immunotherapy; HEPATOCELLULAR-CARCINOMA; CANCER; GLYPICAN-3; SURVIVAL; ANTIBODY; THERAPY;
D O I
10.3892/ijo.2023.5501
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Constantly stimulated by the tumor microenvironment (TME), programmed death 1 (PD-1) is elevated, and it interacts with PD ligand 1 (PD-L1), rendering chimeric antigen receptor (CAR)-T cells dysfunctional. Hence, CAR-T cells immune to PD-1-induced immunosuppression were constructed to improve the function of CAR-T cells in hepatocellular carcinoma (HCC). Double-target CAR-T cells, targeting glypican-3 (GPC3) [a tumour-associated antigen (TAA)] and hindering PD-1-PD-L1 binding, were established. The expression of GPC3, PD-L1, and inhibitory receptors was measured using flow cytometry. The cytotoxicity, cytokine release, and differentiation level of CAR-T cells were determined using lactate dehydrogenase release assay, enzyme-linked immunosorbent assay, and flow cytometry, respectively. HCC cells were targeted and eliminated by double-target CAR-T cells. These double-target CAR-T cells limit PD-1-PD-L1 binding and sustain cytotoxicity to PD-L1(+) HCC cells. The relatively low IR expression and differentiation level in double-target CAR-T cells in tumour tissues induced tumour-suppression and extended survival in PD-L1(+) HCC TX models, as opposed to their single-target counterparts. The results of the present study suggested that the newly constructed double-target CAR-T cells exhibit stronger tumour-suppressing effects in HCC than their single-target counterparts, which are common, suggesting the potential of strengthening CAR-T cell activity in HCC treatment.
引用
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页数:11
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