Immune checkpoint blockade therapy
Immune checkpoint blockade therapy
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DOI：
10.1016/j.jaci.2018.02.042
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发表时间：
2018-11-01
影响因子：
14.2
通讯作者：
Roecken, Martin
中科院分区：
文献类型：
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作者：
Wieder, Thomas;Eigentler, Thomas;Roecken, Martin
免疫检查点是促进或抑制T细胞活化的辅助分子。两种抑制性分子，细胞毒性T淋巴细胞抗原4（CTLA-4）和程序性细胞死亡蛋白1（PD-1），得到了高度关注，因为CTLA-4或PD-1信号传导的抑制提供了第一种显著改善转移性实体癌患者生存的免疫疗法。CTLA-4或PD-1的抑制作用首先在转移性黑色素瘤患者中进行研究并获得批准。阻断免疫检查点在非小细胞肺癌、肾细胞癌、高度突变的胃肠癌等中也是有效的。免疫反应，无论是针对感染还是针对肿瘤，都分为两个阶段：启动阶段和激活阶段，其中免疫系统识别危险信号并被先天信号激活以对抗危险。这种反应是控制感染和癌症的基础，但一旦危险得到控制，就需要关闭，因为这种激活的持续最终会导致严重的组织损伤。因此，免疫系统的每次激活之后是终止阶段，其中内源性免疫抑制分子阻止免疫应答以防止有害损伤。在癌症免疫疗法的情况下，治疗方法经典地增强免疫应答的起始和激活以增加细胞毒性T淋巴细胞（CTL）对抗癌症的出现和功效。与此形成鲜明对比的是，免疫检查点阻断侧重于通过抑制免疫抑制分子来终止免疫应答。因此，它可以阻止免疫应答的终止，甚至唤醒那些在免疫应答期间耗尽的CTL。因此，阻断负调节免疫检查点恢复了耗尽的CTL杀死它们浸润的癌症的能力。此外，它们还将存活的癌细胞推入一种尚不明确的休眠状态。由于该疗法还唤醒自身反应性CTL，因此该疗法的一个缺点是诱导器官特异性自身免疫性疾病。第二个不利因素是过高的药品价格，使有需要的患者放弃学术研究开发的治疗，这损害了进一步的学术治疗开发，并在财政上对公共卫生系统收费。
Immune checkpoints are accessory molecules that either promote or inhibit T-cell activation. Two inhibitory molecules, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non-small-cell lung cancer, renal cell cancers, hypermutated gastrointestinal cancers, and others. Immune responses, whether directed against infections or against tumors, are divided into 2 phases: an initiation phase and an activation phase, where the immune system recognizes a danger signal and becomes activated by innate signals to fight the danger. This reaction is fundamental for the control of infections and cancer, but needs to be turned off once the danger is controlled, because persistence of this activation ultimately causes severe tissue damage. Therefore, each activation of the immune system is followed by a termination phase, where endogenous immune suppressor molecules arrest immune responses to prevent harmful damage. In the case of cancer immune therapies, therapeutic approaches classically enhanced the initiation and activation of immune responses to increase the emergence and the efficacy of cytotoxic T lymphocytes (CTL) against cancers. In sharp contrast, immune checkpoint blockade focuses on the termination of immune responses by inhibiting immune suppressor molecules. It thus prevents the termination of immune responses or even awakes those CTLs that became exhausted during an immune response. Therefore, blocking negatively regulating immune checkpoints restores the capacity of exhausted CTL to kill the cancer they infiltrate. In addition, they drive surviving cancer cells into a still poorly defined state of dormancy. As the therapy also awakes self-reactive CTL, one downside of the therapy is the induction of organ-specific autoimmune diseases. The second downside is the exorbitant drug price that withdraws patients in need from a therapy that was developed by academic research, which impairs further academic treatment development and financially charges the public health system.