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.

Significance: 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. Cancer Discov; 7(11); 1306–19. ©2017 AACR.

This article is highlighted in the In This Issue feature, p. 1201

在早期临床研究中，表达嵌合抗原受体（CAR）的T细胞的过继免疫疗法对实体瘤的成功有限。我们认为将可诱导的共刺激（iCO）分子引入CAR T细胞，该分子由二聚化（CID）结合结构域的化学诱导剂以及MyD88和CD40信号结构域组成，可以改善和控制CAR T细胞的活化。在CID的存在，表达HER2-CARζ和基于CD40-MyD88的/ ICO分子（HER2ζ.iCOT细胞）T细胞具有优异的T细胞增殖，细胞因子产生，和能力依次杀死目标体外相对于HER2ζ。没有CID的iCO T细胞和表达HER2-CAR.CD28ζ的T细胞。带有CID的HER2ζ.iCOT细胞也显着提高了体内存活率在两个异种移植模型中。重复注射CID能够进一步提高HER2ζ.iCOT细胞的体内抗肿瘤活性。因此，在CAR T细胞中表达基于MyD88 / CD40的iCO分子有可能提高CAR T细胞治疗实体瘤的功效。

意义：用小分子药物诱导CAR T细胞中MyD88和CD40的激活不仅增强其效应子功能，从而在临床前实体瘤中产生强大的抗肿瘤活性，而且还可以在输注后对其进行远程控制。巨蟹座Discov; 7（11）；1306–19。©2017 AACR。

本文在本期功能中突出显示。1201