Immune Checkpoint Inhibitors for Cancer Therapy: Clinical Efficacy and Safety
Immune Checkpoint Inhibitors for Cancer Therapy: Clinical Efficacy and Safety
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DOI：
10.2174/156800961506150805145120
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发表时间：
2015-01-01
影响因子：
3
通讯作者：
Shukla, Vivek
中科院分区：
文献类型：
--
作者：
Azoury, Said C.;Straughan, David M.;Shukla, Vivek
癌症免疫治疗的一个重大突破是发现了免疫检查点蛋白，其功能是通过各种机制有效抑制免疫系统。第一个显示出抑制T细胞增殖和IL-2产生的这种分子是细胞毒性T淋巴细胞相关蛋白4（CTLA-4）。有了这一发现，人们转而努力阻断这种抑制途径，试图激活针对癌细胞的休眠T细胞。第一种针对CTLA-4的抗体ipilimumab很快进入临床试验，并于2011年被美国食品和药物管理局（FDA）批准用于治疗转移性黑色素瘤。在易普利姆玛成功之后，研究了其他免疫检查点作为抑制的可能靶点。一种这样的相互作用是程序性细胞死亡-1（PD-1）T细胞受体及其在许多癌细胞上发现的配体，程序性死亡配体1（PD-L1）的相互作用。不幸的是，阻断免疫系统的自然抑制机制的不良影响在临床上表现为腹泻、皮疹和肝炎。尽管如此，免疫检查点抑制剂这一令人兴奋的领域为许多以前预后更差的癌症患者提供了一种潜在的治疗选择。作者旨在提供关于CTLA-4，PD-1和PD-L1靶向治疗在癌症和其他仍处于早期开发阶段的分子治疗中的使用的文献和更新的全面综述。
A major breakthrough in cancer immunotherapy was the discovery of immune checkpoint proteins, which function to effectively inhibit the immune system through various mechanisms. The first of such molecules shown to inhibit both T-cell proliferation and IL-2 production was cytotoxic T-lymphocyte associated protein 4 (CTLA-4). With this discovery, efforts turned to blocking this inhibitory pathway in an attempt to activate dormant T-cells directed at cancer cells. The first antibody directed against CTLA-4, ipilimumab, was quickly ushered into clinical trials and was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic melanoma in 2011. Following the success of ipilimumab, other immune checkpoints were studied as possible targets for inhibition. One such interaction was that of the programmed cell death-1 (PD-1) T-cell receptor and its ligand found on many cancer cells, programmed death-ligand 1 (PD-L1). Unfortunately, the untoward effects of blocking the immune system's natural inhibitory mechanisms have manifested clinically as diarrhea, rash, and hepatitis. Nevertheless, the exciting field of immune checkpoint inhibitors offers a potential curative option for many cancer patients who previously had a more dismal prognosis. The authors aim to provide a comprehensive review of the literature and update on the use of CTLA-4, PD-1 and PD-L1 targeted therapy in the treatment of cancer and other molecules still in the early development phase.