Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma.
Bispecific c-Met/PD-L1 CAR-T Cells Have Enhanced Therapeutic Effects on Hepatocellular Carcinoma.
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DOI：
10.3389/fonc.2021.546586
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发表时间：
2021
影响因子：
4.7
通讯作者：
Ji G
中科院分区：
文献类型：
--
作者：
Jiang W;Li T;Guo J;Wang J;Jia L;Shi X;Yang T;Jiao R;Wei X;Feng Z;Tang Q;Ji G
表达嵌合抗原受体的T细胞，特别是CD 19 CAR-T细胞，在B细胞恶性肿瘤中表现出有效的抗肿瘤活性，但由于抗原逃逸效应和肿瘤微环境等几个因素，其在肝细胞癌中的治疗潜力并不令人鼓舞。为了降低肝癌的抗原逃逸风险，本研究设计并构建了靶向c-Met和PD-L1的双特异性CAR。通过慢病毒转染获得c-Met/PD-L1 CAR-T细胞，并通过流式细胞术分析监测转染效率。LDH释放试验用于阐明c-Met/PD-L1 CAR-T细胞对肝细胞癌细胞的疗效。此外，构建了人肝癌异种移植模型，以检测c-Met/PD-L1 CAR-T细胞的体内抗肿瘤作用。结果表明，成功制备了这种双特异性CAR，与单价c-Met CAR-T细胞或PD-L1 CAR-T细胞相比，用这种双特异性CAR修饰的T细胞显示出对c-Met和PD-L1阳性肝细胞癌细胞的抗肿瘤活性改善，但在体外对肝细胞没有显示出明显的细胞毒性。体内实验表明，与其他组相比，c-Met/PD-L1 CAR-T细胞显著抑制了肿瘤生长，并提高了生存持久性。这些结果表明，设计单链、双特异性c-Met/PD-L1 CAR-T比单价c-Met CAR-T更有效地治疗肝细胞癌。并且这种双特异性c-Met/PD-L1 CAR是合理的，并且可以用当前的T细胞工程技术实现。
T cells expressing chimeric antigen receptors, especially CD19 CAR-T cells have exhibited effective antitumor activities in B cell malignancies, but due to several factors such as antigen escape effects and tumor microenvironment, their curative potential in hepatocellular carcinoma has not been encouraging. To reduce the antigen escape risk of hepatocellular carcinoma, this study was to design and construct a bispecific CAR targeting c-Met and PD-L1. c-Met/PD-L1 CAR-T cells were obtained by lentiviral transfection, and the transfection efficiency was monitored by flow cytometry analysis. LDH release assays were used to elucidate the efficacy of c-Met/PD-L1 CAR-T cells on hepatocellular carcinoma cells. In addition, xenograft models bearing human hepatocellular carcinoma were constructed to detect the antitumor effect of c-Met/PD-L1 CAR-T cells in vivo. The results shown that this bispecific CAR was manufactured successfully, T cells modified with this bispecific CAR demonstrated improved antitumor activities against c-Met and PD-L1 positive hepatocellular carcinoma cells when compared with those of monovalent c-Met CAR-T cells or PD-L1 CAR-T cells but shown no distinct cytotoxicity on hepatocytes in vitro. In vivo experiments shown that c-Met/PD-L1 CAR-T cells significantly inhibited tumor growth and improve survival persistence compared with other groups. These results suggested that the design of single-chain, bi-specific c-Met/PD-L1 CAR-T is more effective than that of monovalent c-Met CAR-T for the treatment of hepatocellular carcinoma., and this bi-specific c-Met/PD-L1 CAR is rational and implementable with current T-cell engineering technology.
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影响因子：
12.4
作者：
Hombach, Andreas A.;Rappl, Gunter;Abken, Hinrich
通讯作者：
Abken, Hinrich
影响因子：
13.5
作者：
Calderaro, Julien;Rousseau, Benoit;Pawlotsky, Jean-Michel
通讯作者：
Pawlotsky, Jean-Michel
DOI：
10.1002/hep.29496
发表时间：
2018-03
期刊：
Hepatology (Baltimore, Md.)
影响因子：
--
作者：
Bouattour M;Raymond E;Qin S;Cheng AL;Stammberger U;Locatelli G;Faivre S
通讯作者：
Faivre S
索拉非尼对亚太地区晚期肝细胞癌患者的疗效和安全性：一项 III 期随机、双盲、安慰剂对照试验
影响因子：
51.1
作者：
Cheng, Ann-Lii;Kang, Yoon-Koo;Guan, Zhongzhen
通讯作者：
Guan, Zhongzhen
影响因子：
3.3
作者：
Frydenlund, Noah;Mahalingam, Meera
通讯作者：
Mahalingam, Meera