Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer.
Keeping Tumors in Check: A Mechanistic Review of Clinical Response and Resistance to Immune Checkpoint Blockade in Cancer.
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DOI：
10.1016/j.jmb.2018.05.030
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发表时间：
2018-07-06
影响因子：
5.6
通讯作者：
Zhang W
中科院分区：
文献类型：
--
作者：
Borcherding N;Kolb R;Gullicksrud J;Vikas P;Zhu Y;Zhang W
免疫检查点是免疫系统的一组不同的抑制信号，在适应性免疫应答和自我耐受中发挥功能作用。这些途径的失调是避免肿瘤细胞免疫破坏的重要机制。免疫检查点阻断（Immune checkpoint blockade，ICB）是一种靶向阻断肿瘤免疫抑制机制，增强抗肿瘤免疫力的方法。细胞毒性T淋巴细胞相关蛋白4（CTLA-4）和程序性细胞死亡1（PD-1）是具有最广泛的基于抗体的疗法的两个免疫检查点。这些疗法已经从有前途的方法发展成为FDA批准的用于许多免疫原性癌症的一线和二线药物。对ICB在血液和实体癌中疗效的新兴研究强调了确定ICB反应和耐药性预测因子的重要性。由于观察到混合反应或同一患者多个病变的不同反应以及诱导治疗后一年内可能发生的延迟反应，因此反应相关性的识别变得复杂。可以影响ICB中的应答和抗性的因素可以阐明免疫激活和抑制的潜在分子机制。这些相同的反应预测因子可以指导识别将从ICB中受益的患者，减少脱靶免疫相关不良事件，并促进使用组合疗法以提高疗效。在这里，我们回顾了免疫检查点治疗的基本原理，单药ICB临床试验的结果，并总结了反应和耐药性的预测因素。
Immune checkpoints are a diverse set of inhibitory signals to the immune system that play a functional role in adaptive immune response and self-tolerance. Dysregulation of these pathways are a vital mechanism in the avoidance of immune destruction by tumor cells. Immune checkpoint blockade (ICB) refers to targeted strategies to disrupt the tumor co-opted immune suppression to enhance anti-tumor immunity. Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death 1 (PD-1) are two immune checkpoints that have the widest range of antibody-based therapies. These therapies have gone from promising approaches to FDA-approved first- and second-line agents for a number of immunogenic cancers. The burgeoning investigations of ICB efficacy in blood and solid cancers have underscored the importance of identifying the predictors of response and resistance to ICB. Identification of response correlates is made complicated by the observations of mixed reactions, or different responses in multiple lesions from the same patient, and delayed responses that can occur over a year after the induction therapy. Factors that can influence response and resistance in ICB can illuminate underlying molecular mechanisms of immune activation and suppression. These same response predictors can guide the identification of patients who would benefit from ICB, reduce off-target immune-relate adverse events, and facilitate the use of combinatorial therapies to increase efficacy. Here we review the underlying principles of immune checkpoint therapy, results of single-agent ICB clinical trials, and summarize the predictors of response and resistance.
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