Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models.
Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models.
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在CAR T细胞中，MyD88和CD40的诱导激活在临床前实体瘤模型中导致可控且有效的抗肿瘤活性。
DOI：
10.1158/2159-8290.cd-17-0263
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发表时间：
2017-11
期刊：
影响因子：
28.2
通讯作者：
Gottschalk S
中科院分区：
文献类型：
--
作者：
Mata M;Gerken C;Nguyen P;Krenciute G;Spencer DM;Gottschalk S
在早期临床研究中，用表达嵌合抗原受体（CAR）的T细胞进行的连续免疫疗法对实体瘤的成功有限。我们推断，向CAR T细胞中引入由二聚化（CID）结合结构域的化学诱导剂和MyD 88和CD 40信号传导结构域组成的诱导型共刺激（iCO）分子将改善和控制CAR T细胞活化。在存在CID的情况下，表达HER 2-CAR. CD 28+和基于MyD 88/CD 40的iCO分子的T细胞（HER 2 +.iCO T细胞）相对于不含CID的HER 2 +.iCO T细胞和表达HER 2-CAR. CD 28+的T细胞具有上级T细胞增殖、细胞因子产生和体外顺序杀死靶标的能力。在两种异种移植物模型中，具有CID的HER 2 α iCO T细胞也显著改善了体内存活。CID的重复注射能够进一步增加体内HER 2 α.iCO T细胞的抗肿瘤活性。因此，在CAR T细胞中表达基于MyD 88/CD 40的iCO分子具有改善实体瘤CAR T细胞疗法方法的功效的潜力。用小分子药物诱导CAR T细胞中MyD 88和CD 40的活化不仅增强了它们的效应功能，从而在临床前实体瘤中产生了有效的抗肿瘤活性，而且还使它们能够在输注后进行远程控制。
Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CAR) has had limited success for solid tumors in early-phase clinical studies. We reasoned that introducing into CAR T cells an inducible costimulatory (iCO) molecule consisting of a chemical inducer of dimerization (CID)–binding domain and the MyD88 and CD40 signaling domains would improve and control CAR T-cell activation. In the presence of CID, T cells expressing HER2–CARζ and a MyD88/CD40–based iCO molecule (HER2ζ.iCO T cells) had superior T-cell proliferation, cytokine production, and ability to sequentially kill targets in vitro relative to HER2ζ.iCO T cells without CID and T cells expressing HER2–CAR.CD28ζ. HER2ζ.iCO T cells with CID also significantly improved survival in vivo in two xenograft models. Repeat injections of CID were able to further increase the antitumor activity of HER2ζ.iCO T cells in vivo. Thus, expressing MyD88/CD40–based iCO molecules in CAR T cells has the potential to improve the efficacy of CAR T-cell therapy approaches for solid tumors. Inducible activation of MyD88 and CD40 in CAR T cells with a small-molecule drug not only enhances their effector function, resulting in potent antitumor activity in preclinical solid tumors, but also enables their remote control post infusion.