Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany.
Curr Mol Med. 2013 Aug;13(7):1079-88. doi: 10.2174/1566524011313070003.
Adoptive cell therapy has shown impressive efficacy to combat cancer in early phase clinical trials, in particular when T cells engineered to specifically target tumor cells were applied. The patient's T cells are genetically equipped with a chimeric antigen receptor (CAR) which allows them to be redirected in a predefined manner towards virtually any target; by using an antibody-derived domain for binding, CAR T cells can be redirected in a major histocompatibility complex (MHC) dependent and independent fashion. The CAR also provides the stimuli required to induce and maintain T cell activation. Recent clinical data sustain the notion that strong costimulation in conjunction with the primary activation signal is crucial for lasting therapeutic efficacy of CAR T cells. However, costimulation is a double-edged sword and the impact of the individual costimuli to optimize T cell activation is still under debate; some general rules are emerging. The review summarizes how costimulation modulates, improves and prolongs the redirected anti-tumor T cell response and how the same costimulatory signals may contribute to unintended side effects including "cytokine storm" and T cell repression. Upcoming strategies to break the activation/repression circle by using CAR's with modified costimulatory signals are also discussed.
过继细胞疗法在早期临床试验中显示出对抗癌症的显著疗效，尤其是当应用专门针对肿瘤细胞的工程化 T 细胞时。患者的 T 细胞经过基因改造，配备了嵌合抗原受体（CAR），使其能够以预先定义的方式被重新定向到几乎任何目标；通过使用源自抗体的结构域进行结合，CAR T 细胞可以以主要组织相容性复合体（MHC）依赖和非依赖的方式被重新定向。CAR 还提供了诱导和维持 T 细胞激活所需的刺激。最近的临床数据支持这样一种观点，即强烈的共刺激与主要激活信号一起对于 CAR T 细胞的持久治疗效果至关重要。然而，共刺激是一把双刃剑，优化 T 细胞激活的各个共刺激物的影响仍存在争议；一些一般规则正在出现。这篇综述总结了共刺激如何调节、改善和延长重定向的抗肿瘤 T 细胞反应，以及相同的共刺激信号如何导致意外的副作用，包括“细胞因子风暴”和 T 细胞抑制。还讨论了使用具有修饰的共刺激信号的 CAR 来打破激活/抑制循环的即将到来的策略。
