Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency
Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency
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DOI：
10.1038/s41591-018-0290-5
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发表时间：
2019-01-01
期刊：
影响因子：
82.9
通讯作者：
Sadelain, Michel
中科院分区：
文献类型：
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作者：
Feucht, Judith;Sun, Jie;Sadelain, Michel
嵌合抗原受体（CARs）是一种合成受体，其靶向T细胞并对其进行重编程以获得增强的抗肿瘤特性(1)。包含CD28和CD3 zeta信号基序(2)的cd19特异性car在难治性白血病（3-5）和淋巴瘤(6)患者中引起了显著的反应，最近获得了美国食品和药物管理局(7)的批准(7)。尽管这些car赋予T细胞的持久性有限，但它们编程了高效的效应功能，介导了有效的肿瘤消除（4,8）。在不影响其效力的情况下延长其功能持久性应该会改善目前的CAR疗法。强烈的T细胞激活驱动耗竭（9,10），这可能因CD28和CD3 zeta信号的冗余（11,12）以及第二代car的结构所赋予的时空限制而加剧(2)。因此，我们假设校准基于cd28的car的激活电位会对T细胞功能和分化进行差异重编程。在这里，我们展示了CAR编码一个基于酪氨酸的单一免疫受体激活基序，通过平衡效应和记忆程序将T细胞引导到不同的命运，从而产生具有增强治疗效果的CAR设计。
Chimeric antigen receptors (CARs) are synthetic receptors that target and reprogram T cells to acquire augmented antitumor properties(1). CD19-specific CARs that comprise CD28 and CD3 zeta signaling motifs(2) have induced remarkable responses in patients with refractory leukemia(3-5) and lymphoma(6) and were recently approved by the US Food and Drug Administration(7). These CARs program highly performing effector functions that mediate potent tumor elimination(4,8) despite the limited persistence they confer on T cells(3-6,8). Extending their functional persistence without compromising their potency should improve current CAR therapies. Strong T cell activation drives exhaustion(9,10), which may be accentuated by the redundancy of CD28 and CD3 zeta signaling(11,12) as well as the spatiotemporal constraints imparted by the structure of second-generation CARs(2). Thus, we hypothesized that calibrating the activation potential of CD28-based CARs would differentially reprogram T cell function and differentiation. Here, we show that CARs encoding a single immunoreceptor tyrosine-based activation motif direct T cells to different fates by balancing effector and memory programs, thereby yielding CAR designs with enhanced therapeutic profiles.