Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells.
Optimization of the proliferation and persistency of CAR T cells derived from human induced pluripotent stem cells.
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DOI：
10.1038/s41551-022-00969-0
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发表时间：
2023-01
影响因子：
28.1
通讯作者：
Kaneko S
中科院分区：
文献类型：
--
作者：
Ueda T;Shiina S;Iriguchi S;Terakura S;Kawai Y;Kabai R;Sakamoto S;Watanabe A;Ohara K;Wang B;Xu H;Minagawa A;Hotta A;Woltjen K;Uemura Y;Kodama Y;Seno H;Nakatsura T;Tamada K;Kaneko S
嵌合抗原受体(CAR)T细胞免疫疗法对实体瘤的疗效依赖于肿瘤部位T细胞的聚集、增殖和持久性。在这里，我们表明，CD8CAR细胞毒T细胞在实体瘤中的增殖可以通过从单个人类诱导多能干细胞克隆中衍生和扩增来增强，该克隆携带一种被选择用于有效分化的CAR。我们还表明，通过从基因上敲除抑制抗原受体信号转导的二酰甘油激酶，以及通过转导编码膜结合的白细胞介素15(IL-15)及其受体亚单位IL-15Rα的基因，可以进一步增强肿瘤中效应细胞的增殖和持久性。在多种荷瘤动物模型中，基因工程的HiPSC来源的CAR T细胞导致了与携带相同CAR的原始CD8 T细胞相似的治疗结果。从多能干细胞来源的效应器CAR T细胞的优化可能有助于开发用于治疗实体瘤的长效抗原特异性T细胞免疫疗法。来自人类诱导的多能干细胞的细胞毒性CAR T细胞可以通过基因工程来增强实体肿瘤的增殖和持久性。
The effectiveness of chimaeric antigen receptor (CAR) T-cell immunotherapies against solid tumours relies on the accumulation, proliferation and persistency of T cells at the tumour site. Here we show that the proliferation of CD8αβ cytotoxic CAR T cells in solid tumours can be enhanced by deriving and expanding them from a single human induced-pluripotent-stem-cell clone bearing a CAR selected for efficient differentiation. We also show that the proliferation and persistency of the effector cells in the tumours can be further enhanced by genetically knocking out diacylglycerol kinase, which inhibits antigen-receptor signalling, and by transducing the cells with genes encoding for membrane-bound interleukin-15 (IL-15) and its receptor subunit IL-15Rα. In multiple tumour-bearing animal models, the engineered hiPSC-derived CAR T cells led to therapeutic outcomes similar to those of primary CD8 T cells bearing the same CAR. The optimization of effector CAR T cells derived from pluripotent stem cells may aid the development of long-lasting antigen-specific T-cell immunotherapies for the treatment of solid tumours. Cytotoxic CAR T cells derived from human induced pluripotent stem cells can be genetically engineered for enhanced proliferation and persistency in solid tumours.
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影响因子：
7.3
作者：
Ali AK;Nandagopal N;Lee SH
通讯作者：
Lee SH
影响因子：
5.9
作者：
Kagita A;Lung MSY;Xu H;Kita Y;Sasakawa N;Iguchi T;Ono M;Wang XH;Gee P;Hotta A
通讯作者：
Hotta A
DOI：
10.1158/1078-0432.ccr-11-0503
发表时间：
2011-08-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Klebanoff CA;Gattinoni L;Palmer DC;Muranski P;Ji Y;Hinrichs CS;Borman ZA;Kerkar SP;Scott CD;Finkelstein SE;Rosenberg SA;Restifo NP
通讯作者：
Restifo NP
影响因子：
82.9
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
82.9
作者：
Gattinoni L;Lugli E;Ji Y;Pos Z;Paulos CM;Quigley MF;Almeida JR;Gostick E;Yu Z;Carpenito C;Wang E;Douek DC;Price DA;June CH;Marincola FM;Roederer M;Restifo NP
通讯作者：
Restifo NP