Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells.
Identification of chimeric antigen receptors that mediate constitutive or inducible proliferation of T cells.
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DOI：
10.1158/2326-6066.cir-14-0186
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发表时间：
2015-04
影响因子：
10.1
通讯作者：
June CH
中科院分区：
文献类型：
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作者：
Frigault MJ;Lee J;Basil MC;Carpenito C;Motohashi S;Scholler J;Kawalekar OU;Guedan S;McGettigan SE;Posey AD Jr;Ang S;Cooper LJ;Platt JM;Johnson FB;Paulos CM;Zhao Y;Kalos M;Milone MC;June CH
本研究比较了编码由CD 28、ICOS和4-1BB组成的信号结构域的第二代嵌合抗原受体。在这里，我们报告了某些汽车赋予T细胞进行长期自主增殖的能力。用编码一些汽车的慢病毒载体转导原代人T细胞导致在通过TCR的单次刺激后持续增殖长达三个月。持续的数值扩增不依赖于同源抗原，并且在TCR和CD 28的单次刺激后不需要添加外源性细胞因子或饲养细胞。来自基因阵列和功能测定的结果将持续的细胞因子分泌和T-bet、EOMES和加塔-3的表达与效果联系起来。尚未报道原代T细胞中内源性IL 2基因座的持续表达。持续增殖依赖于CAR结构和高表达，后者是必要的，但不是充分的。该机制涉及通过NF-kB、Akt、Erk和NFAT的组成性信号传导。增殖的CAR T细胞保留了不同的TCR库，并且未观察到细胞转化。具有组成性生长表型的汽车显示出较差的抗肿瘤作用和体内植入。因此，具有非组成型生长表型的汽车的设计可能是改善CAR T细胞的功效和植入的策略。赋予组成型或非组成型生长模式的汽车的鉴定可以解释CAR T细胞在临床试验中具有不同存活模式的观察结果。
This study compared second generation chimeric antigen receptors encoding signaling domains composed of CD28, ICOS and 4-1BB. Here we report that certain CARs endow T cells with the ability to undergo long-term autonomous proliferation. Transduction of primary human T-cell with lentiviral vectors encoding some of the CARs resulted in sustained proliferation for up to three months following a single stimulation through the TCR. Sustained numeric expansion was independent of cognate antigen and did not require the addition of exogenous cytokines or feeder cells after a single stimulation of the TCR and CD28. Results from gene array and functional assays linked sustained cytokine secretion and expression of T-bet, EOMES and GATA-3 to the effect. Sustained expression of the endogenous IL2 locus has not been reported in primary T cells. Sustained proliferation was dependent on CAR structure and high expression, the latter of which was necessary but not sufficient. The mechanism involves constitutive signaling through NF-kB, Akt, Erk and NFAT. The propagated CAR T cells retained a diverse TCR repertoire and cellular transformation was not observed. The CARs with a constitutive growth phenotype displayed inferior antitumor effects and engraftment in vivo. Therefore the design of CARs that have a non-constitutive growth phenotype may be a strategy to improve efficacy and engraftment of CAR T cells. The identification of CARs that confer constitutive or non-constitutive growth patterns may explain observations that CAR T cells have differential survival patterns in clinical trials.