胃癌免疫检查点抑制剂作用机制及最新研究进展

doi:10.11904/j.issn.1002-3070.2019.04.016

摘要/Abstract

摘要： 胃癌治疗有限,预后较差。目前肿瘤免疫治疗因其显著的生存获益已成为除手术、化疗、放疗及靶向治疗之外有效的新型肿瘤治疗手段。免疫检查点抑制剂作为肿瘤免疫治疗的之一,已被批准用于多种肿瘤的治疗,提示胃癌免疫治疗时代已经到来。本文介绍了免疫治疗中免疫检查点抑制剂的作用机制及相关研究进展。

关键词: 胃癌, 免疫治疗, 免疫检查点抑制剂

Abstract: The treatment of gastric cancer is limited and the prognosis is poor.Tumor immunotherapy has been an effective new treatment for cancer in addition to surgery,chemotherapy,radiotherapy and targeted therapy because of its remarkable survival benefit.As one of the methods of tumor immunotherapy,immunological checkpoint inhibitors have been approved for the treatment of various tumors,suggesting that the era of gastric cancer immunotherapy has arrived.This article describes the mechanism of action and related research progress of immunological checkpoint inhibitors in immunotherapy.

Key words: Gastric cancer, Immunotherapy, Immunological checkpoint inhibitors

中图分类号:

R735.2

姚洋张艳桥. 胃癌免疫检查点抑制剂作用机制及最新研究进展[J]. 实用肿瘤学杂志, 2019, 33(4): 371-375.

YAO Yang, ZHANG Yanqiao. Mechanism and recent progress of gastric cancer in immunological checkpoint inhibitors[J]. Journal of Practical Oncology, 2019, 33(4): 371-375.

参考文献

1 Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA Cancer J Clin,2016,66(2):115-132.
2 Bray F,Ferlay J,Soerjomataram I,et al.Global cancer statistics 2018:GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J].CA Cancer J Clin,2018,68(6):394-424.
3 丁乃清,魏嘉,陈仿军,等.胃癌免疫治疗临床研究进展[J].肿瘤综合治疗电子杂志,2018,4(2):1-5.
4 Abdel-Rahman O,Helbling D,Schmidt J,et al.Treatment-related death in cancer patients treated with immune checkpoint inhibitors:A systematic review and meta-analysis[J].Clinical Oncology,2017,29(4):218-230.
5 苗素平,郭二亮,裴荣,等.miRNA调节免疫检查点在肿瘤治疗中的研究进展[J].实用肿瘤学杂志,2018,32(1):57-62.
6 卢伸,苏丹.免疫检查点阻断用于肿瘤治疗的研究进展[J].实用肿瘤杂志,2016,31(1):19-23.
7 曾玉兰,刘洋洋,梁金燕,等.免疫检查点抑制剂耐药机制及耐药后治疗策略的研究进展[J].实用肿瘤学杂志,2017,31(4):353-358.
8 Chen L,Flies DB.Molecular mechanisms of T cell co-stimulation and co-inhibition[J].Nature Reviews Immunology,2013,13(4):227-242.
9 王晓静.胃癌的免疫治疗进展[D].石家庄:河北医科大学,2018.
10 Yokosuka T,Takamatsu M,Kobayashi-Imanishi W,et al.Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2[J].J Exp Med,2012,209(6):1201-1217.
11 Muro K,Chung HC,Shankaran V,et al.Pembrolizumab for patients with PD-L1-positive advanced gastric cancer(KEYNOTE-012):a multicentre,open-label,phase 1b trial[J].Lancet Oncology,2016,17(6):717-726.
12 Wainberg ZA,Jalal S,Muro K,et al.KEYNOTE-059 Update:Efficacy and safety of pembrolizumab alone or in combination with chemotherapy in patients with advanced gastric or gastroesophageal(G/GEJ)cancer[J].Ann Oncol,2017,28(suppl5):616-617.
13 Catenacci DV,Wainberg Z,Fuchs CS,et al.KEYNOTE-059 cohort 3:safety efficacy of pembrolizumab monotherapy for first-line treatment of patients(pts)with PD-L1-positive advanced gastric/gastroesophageal(G/GEJ)cancer[J].Ann Oncol,2017,28(suppl3):153.
14 Fuchs CS,Doi T,Jang RW,et al.Safety and efficacy of pembrolizumab monotherapy in patients with previously treated advanced gastric and gastroesophageal junction cancer[J].JAMA Oncology,2018,4(5):e180013.
15 Shitara K,zgüroˇglu M,Bang YJ,et al.Pembrolizumab versus paclitaxel for previously treated,advanced gastric or gastro-oesophageal junction cancer(KEYNOTE-061):a randomised,open-label,controlled,phase 3 trial[J].The Lancet,2018,392(10142):123-133.
16 Ohtsu A,Tabernero J,Bang YJ,et al.Pembrolizumab versus paclitaxel as second-line therapy for advanced gastric or gastroesophageal junction(GEJ)adenocarcinoma:Phase 3 KEYNOTE-061 study[J].J Clin Oncol,2016,34(15):4137.
17 Kang YK,Boku N,Satoh T,et al.Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to,or intolerant of,at least two previous chemotherapy regimens(ONO-4538-12,ATTRACTION-2):a randomised,double-blind,placebo-controlled,phase 3 trial[J].Lancet,2017,390(10111):2461-2471.
18 Janjigian YY,Bendell J,Calvo E,et al.Check Mate-032:phase Ⅰ/Ⅱ open-label study of safety and activity of nivolumab(nivo)alone or with ipilimumab(ipi)in advanced and metastatic(A/M)gastric cancer(GC)[J].J Clin Oncol,2016,34(15):4010.
19 Dung TL,Johanna CB,Emiliano C,et al.Safety and activity of nivolumab monotherapy in advanced and metastatic gastric or gastroesophageal junction cancer(GC/GEC):results from the CheckMate-032 Study[J].J Clin Oncol,2016,34(suppl 4S):6.
20 Heery CR,O′Sullivancoyne G,Madan RA,et al.Avelumab for metastatic or locally advanced previously treated solid tumours(JAVELIN Solid Tumor):a phase 1a,multicohort,dose-escalation trial[J].Lancet Oncology,2017,18(5):587.
21 Taieb J,Moehler M,Boku N,et al.Evolution of checkpoint inhibitors for the treatment of metastatic gastric cancers:Current status and future perspectives[J].Cancer Treatment Reviews,2018,66:104-113.
22 Eric VC,Lucjan W,Keun-Wook L,et al.P-282JAVELIN Gastric 300:Phase 3 trial of avelumab(anti-PD-L1 antibody)+best supportive care(BSC)vs BSC±chemotherapy as third-line treatment for advanced gastric or gastroesophageal junction cancer[J].Ann Oncol,2016,27(suppl 2):82.
23 Segal NH,Hamid O,Hwu W.A phase I multi-arm dose-expansion study of the anti-programmed cell death-ligand-1(PD-L1)antibody MEDI4736:Preliminary data[J].Ann Oncol,2014,25(suppl4):361-372.
24 Bang YJ,Cho JY,Kim YH,et al.Efficacy of sequential ipilimumab monotherapy vs best supportive care for unresectable locally advanced/metastatic gastric or gastroesophageal junction cancer[J].Clin Cancer Res,2017,23(19):5671.
25 Ralph C,Elkord E,Burt DJ,et al.Modulation of lymphocyte regulation for cancer therapy:A phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma[J].Clin Cancer Res,2010,16(5):1662-1672.

[1]	秦文,赵楠楠,韩永焕,徐亚君. ZNF436在胃癌中的表达及调控WNT/β-catenin对胃癌细胞迁移及侵袭的影响[J]. 实用肿瘤学杂志, 2019, 33(3): 222-227.
[2]	孟海,杜观祥,朱利玲,汤琪云. WEE1在胃癌组织中的表达及对患者预后的影响[J]. 实用肿瘤学杂志, 2019, 33(3): 239-243.
[3]	刘佳音,燕飞虎,张艳桥. 凋亡基因Caspase3和Caspase7单核苷酸多态性与胃癌遗传易感性研究[J]. 实用肿瘤学杂志, 2019, 33(3): 250-255.
[4]	白玉贤, 马仲娟, 苏颖玲, 慕安国, 谢蕊. 胃癌患者FHIT、hMLH1、p16、RAR-beta、Reprimo和TIMP3基因的甲基化研究[J]. 实用肿瘤学杂志, 2019, 33(1): 8-13.
[5]	张凤春, 江莺, 刘照南, 闫宁宁, 崔洪全, 徐迎春. 系统性炎症相关指标中性粒细胞/淋巴细胞比值及血小板/淋巴细胞比值在根治性切除术后的胃癌患者的预后意义[J]. 实用肿瘤学杂志, 2019, 33(1): 34-39.
[6]	张宝综述, 郑志超校审. 进展期胃癌淋巴结清扫研究进展[J]. 实用肿瘤学杂志, 2019, 33(1): 78-81.
[7]	唐淑丽, 何匡邦, 张纯慧, 程佳楠, 张艳桥. 胃癌组织中miR-320a和CYLD的表达及与临床病理特征及预后的关系[J]. 实用肿瘤学杂志, 2018, 32(6): 538-544.
[8]	伊庆亭, 张红军, 姜韬, 傅佳雷, 华明涛. 多烯磷脂酰胆碱在裸鼠模型中逆转胃癌细胞奥沙利铂耐药的作用及机制研究[J]. 实用肿瘤学杂志, 2018, 32(5): 385-390.
[9]	孙祖刚, 王哲, 陈怀安, 刘硕, 苗文隆. 诱发膀胱癌的常见慢性炎症因素及其免疫治疗的研究进展[J]. 实用肿瘤学杂志, 2018, 32(4): 357-361.
[10]	张婷, 贾迪(综述), 杨丹(审校). 骨肉瘤的生物学治疗进展[J]. 实用肿瘤学杂志, 2018, 32(3): 254-257.
[11]	姚强, 王宽, 薛英威. SRC1在胃癌中的表达及其与预后的关系[J]. 实用肿瘤学杂志, 2018, 32(2): 97-102.
[12]	余嘉惠, 刘煊, 李琦, 陆烨, 岳小强. 长链非编码RNA在胃癌中的调控机制及中药对其作用的研究概况[J]. 实用肿瘤学杂志, 2018, 32(1): 47-52.
[13]	苗素平, 郭二亮, 裴荣, 姜寰宇, 苗素生. miRNA调节免疫检查点在肿瘤治疗中的研究进展[J]. 实用肿瘤学杂志, 2018, 32(1): 57-62.
[14]	刘国慧, 谷安鑫, 殷洪涛, 曹阳, 贺云龙, 王春波, 鄂明艳. 原苏木素A对胃癌SGC-7901细胞系放疗增敏作用的研究[J]. 实用肿瘤学杂志, 2017, 31(6): 500-505.
[15]	张纯慧, 刘霞, 徐京京, 周艳华, 赵娟, 李志伟, 张艳桥. 633例胃癌患者临床病理特征及生存分析[J]. 实用肿瘤学杂志, 2017, 31(5): 396-404.