Department of Clinical Pharmacology, Genentech Research and Early Development, South San Francisco, USA.
Ann Oncol. 2018 Jan 1;29(1):71-83. doi: 10.1093/annonc/mdx686.
Checkpoint receptor blockers, known to act by blocking the pathways that inhibit immune cell activation and stimulate immune responses against tumor cells, have been immensely successful in the treatment of cancer. Among several checkpoint receptors of immune cells, cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), programmed cell death protein-1 (PD-1), T-cell immunoglobulin and ITIM domain (TIGIT), T-cell immunoglobulin-3 (TIM-3) and lymphocyte activation gene 3 (LAG-3) are the most commonly targeted checkpoints for cancer immunotherapy. Six drugs including one CTLA-4 blocker (ipilimumab), two PD-1 blockers (nivolumab and pembrolizumab) and three PD-L1 blockers (atezolizumab, avelumab and durvalumab) are approved for the treatment of different types of cancers including both solid tumors such as melanoma, lung cancer, head and neck cancer, bladder cancer and Merkel cell cancer as well as hematological tumors such as classic Hodgkin's lymphoma. The main problem with checkpoint blockers is that only a fraction of patients respond to the therapy. Insufficient immune activation is considered as one of the main reason for low response rates and combination of checkpoint blockers has been proposed to increase the response rates. The combination of checkpoint blockers was successful in melanoma but had significant adverse events. A combination that is selected based on the mechanistic differences between checkpoints and the differences in expression of checkpoints and their ligands in the tumor microenvironment could have a synergistic effect in a given cancer subtype and also have a manageable safety profile. This review aims to help in design of optimal checkpoint blocker combinations by discussing the mechanistic details and outlining the subtle differences between major checkpoints targeted for cancer immunotherapy.
检查点受体阻滞剂通过阻断抑制免疫细胞激活和刺激针对肿瘤细胞免疫反应的途径，在癌症治疗中取得了巨大成功。在免疫细胞的几种检查点受体中，细胞毒性 T 淋巴细胞相关蛋白 4（CTLA-4）、程序性细胞死亡蛋白 1（PD-1）、T 细胞免疫球蛋白和 ITIM 结构域（TIGIT）、T 细胞免疫球蛋白-3（TIM-3）和淋巴细胞激活基因 3（LAG-3）是癌症免疫治疗中最常用的靶向检查点。六种药物包括一种 CTLA-4 阻滞剂（伊匹单抗）、两种 PD-1 阻滞剂（纳武单抗和帕博利珠单抗）和三种 PD-L1 阻滞剂（阿替利珠单抗、avelumab 和度伐鲁单抗）被批准用于治疗包括黑色素瘤、肺癌、头颈部癌症、膀胱癌和 Merkel 细胞癌等实体瘤以及经典霍奇金淋巴瘤等血液肿瘤在内的多种癌症。检查点阻滞剂的主要问题是只有一部分患者对治疗有反应。免疫激活不足被认为是低反应率的主要原因之一，因此提出了联合使用检查点阻滞剂以提高反应率。在黑色素瘤中，联合使用检查点阻滞剂取得了成功，但有显著的不良反应。基于检查点之间的机制差异以及肿瘤微环境中检查点及其配体的表达差异，选择联合使用检查点阻滞剂可能在特定癌症亚型中具有协同作用，同时具有可管理的安全性特征。本综述旨在通过讨论机制细节并概述癌症免疫治疗中针对的主要检查点之间的细微差异，帮助设计最佳的检查点阻滞剂联合方案。
