Christodoulou Maria-Ioanna, Zaravinos Apostolos
Department of Life Sciences, School of Sciences, European University Cyprus, 1516, Nicosia, Cyprus.
Department of Life Sciences, School of Sciences, European University Cyprus, 1516, Nicosia, Cyprus; College of Medicine, Member of QU Health, Qatar University, Doha, Qatar.
Crit Rev Immunol. 2019;39(5):379-408. doi: 10.1615/CritRevImmunol.2020033340.
Background-The development of immune checkpoint blockers, primarily comprising the anti-PD-1/an-ti-PD-L1 and anti-CTLA-4 monoclonal antibodies, has formed the therapeutic landscape of quite a few different cancer types. In spite of the great clinical results produced by some inhibitors in some cases, most cancer patients still present de novo or adaptive resistance, and thus, the overall efficacy of this type of immunotherapy is not sufficient. Here, we explore emerging immune checkpoint molecules apart from anti-PD-1/anti-PD-L1 and anti-CTLA-4, presently being used in the clinical setting as mono- or combinatorial therapy against various cancer types. Methods-Primary publications with results between January 2014 and December 2019 were investigated on PubMed. ClinicalTrials.gov was screened for finding phase I/II/III cancer trials on the use of new immune checkpoint targets, including LAG-3, TIM-3, TIGIT, and VISTA, which are active (recruiting or not) or completed. Results-We recapitulate the clinical data associated with these immune checkpoint inhibitors and analyze their application prospects. The investigation about such emerging molecules has produced encouraging outcomes in preclinical studies and/or clinical trials. Conclusions-Although monotherapy treatment has yielded impressive results in some cases, the current attempts emphasize more the design of combinatorial immune checkpoint inhibition that targets non-redundant pathways to achieve a synergistic effect against cancer cells. It seems that such new combinatorial checkpoint inhibition schemes will achieve better outcomes for the patients than the ones witnessed with CTLA-4 or PD-1/PD-L1 blockers.
背景——免疫检查点阻断剂的发展，主要包括抗程序性死亡蛋白1（anti-PD-1）/抗程序性死亡配体1（anti-PD-L1）和抗细胞毒性T淋巴细胞相关蛋白4（anti-CTLA-4）单克隆抗体，已经形成了多种不同癌症类型的治疗格局。尽管某些抑制剂在某些情况下产生了显著的临床效果，但大多数癌症患者仍表现出原发性或适应性耐药，因此，这类免疫疗法的总体疗效并不理想。在此，我们探索除anti-PD-1/anti-PD-L1和anti-CTLA-4之外的新兴免疫检查点分子，目前这些分子正在临床中作为单药或联合疗法用于治疗各种癌症类型。
方法——在PubMed上检索了2014年1月至2019年12月期间有结果的主要出版物。在ClinicalTrials.gov上进行筛选，以查找关于使用新免疫检查点靶点（包括淋巴细胞激活基因3（LAG-3）、T细胞免疫球蛋白和粘蛋白结构域3（TIM-3）、T细胞免疫球蛋白和免疫受体酪氨酸抑制基序结构域（TIGIT）和VISTA）的I/II/III期癌症试验，这些试验处于活跃状态（正在招募或已停止招募）或已完成。
结果——我们总结了与这些免疫检查点抑制剂相关的临床数据，并分析了它们的应用前景。对这类新兴分子的研究在临床前研究和/或临床试验中产生了令人鼓舞的结果。
结论——尽管单药治疗在某些情况下取得了令人瞩目的结果，但目前的尝试更多地强调联合免疫检查点抑制的设计，即针对非冗余途径以实现对癌细胞的协同作用。似乎这种新的联合检查点抑制方案将为患者带来比细胞毒性T淋巴细胞相关蛋白4（CTLA-4）或程序性死亡蛋白1（PD-1）/程序性死亡配体1（PD-L1）阻断剂更好的治疗效果。
