Tyrosine kinase signaling-independent MET-targeting with CAR-T cells.
Tyrosine kinase signaling-independent MET-targeting with CAR-T cells.
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DOI：
10.1186/s12967-023-04521-9
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发表时间：
2023-10-01
影响因子：
7.4
通讯作者：
Xie, Qian
中科院分区：
文献类型：
--
作者：
Qin, Anna;Qin, Yuan;Lee, Joseph;Musket, Anna;Ying, Mingyao;Krenciute, Giedre;Marincola, Francesco M.;Yao, Zhi Q.;Musich, Phillip R.;Xie, Qian
关键词：
肿瘤免疫治疗的最新进展鼓励嵌合抗原受体(CAR)T细胞治疗在实体瘤中的扩大，包括肝细胞癌(HCC)。MET受体酪氨酸激酶的过度表达在肝细胞癌中很常见；然而，MET抑制剂只有在MET处于活性状态时才有效，这使得患者分层困难。特异性MET靶向CAR-T细胞有望靶向MET过表达的肝细胞癌，而不管信号通路的活性如何。构建以CD28ζ或4-1BBζ为共刺激结构域的MET特异性CAR。本研究比较了正常人和肝癌患者来源的MET-CAR-T细胞在体外对不同MET活性的肝癌细胞的杀伤活性和细胞因子的释放，以及在体内原位异种移植模型中对肿瘤生长的抑制作用。来源于HS和肝癌患者的MET-CAR.CD28ζ和MET-CAR.4-1BBζT细胞可特异性杀伤MET阳性的肝癌细胞。MET阳性肝癌细胞体外刺激时，MET-CAR.CD28ζT细胞比MET-CAR.4-1BBζT细胞有更高水平的细胞因子释放和细胞程序性死亡蛋白1(PD-1)的表达。在体内分析时，与MET-CAR.4-1BBζT细胞相比，MET-CAR.CD28ζT细胞更有效地抑制小鼠肝癌原位肿瘤的生长。我们建立并鉴定了MET特异性CAR-T细胞，用于靶向MET过度表达的肝细胞癌，而不考虑MET的激活。与MET-CAR.4-1BBζ相比，MET-CAR.CD28ζT细胞显示出更高的抗肝癌活性，但也有更高的T细胞耗竭水平。虽然MET-CAR.CD28ζ是进一步发展的首选，但克服MET-CAR-T细胞的耗竭是提高其体内疗效所必需的。网上版载有补充材料，可在10.1186/s12967-023-04521-9查阅。
Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo. The online version contains supplementary material available at 10.1186/s12967-023-04521-9.
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影响因子：
158.5
作者：
Llovet, Josep M.;Ricci, Sergio;Bruix, Jordi
通讯作者：
Bruix, Jordi
影响因子：
64.5
作者：
CHISARI, FV;KLOPCHIN, K;PALMITER, RD
通讯作者：
PALMITER, RD
影响因子：
4.7
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
通讯作者：
Ji G
影响因子：
37.3
作者：
Corso S;Ghiso E;Cepero V;Sierra JR;Migliore C;Bertotti A;Trusolino L;Comoglio PM;Giordano S
通讯作者：
Giordano S
DOI：
10.1056/nejmoa1717002
发表时间：
2018-07-05
期刊：
The New England journal of medicine
影响因子：
--
作者：
Abou-Alfa GK;Meyer T;Cheng AL;El-Khoueiry AB;Rimassa L;Ryoo BY;Cicin I;Merle P;Chen Y;Park JW;Blanc JF;Bolondi L;Klümpen HJ;Chan SL;Zagonel V;Pressiani T;Ryu MH;Venook AP;Hessel C;Borgman-Hagey AE;Schwab G;Kelley RK
通讯作者：
Kelley RK