免疫检查点抑制剂疗效预测因素分析

目的 近年来,以程序性死亡受体(programmed death-1,PD-1)和细胞毒T淋巴细胞相关抗原4(cytotoxic T lymphocyte-associated antigen-4,CTLA-4)抑制剂为代表的免疫检查点抑制剂在晚期黑色素瘤和肺癌等肿瘤中取得了显著疗效.开发可预测其疗效的生物标志物有助于免疫检查点抑制剂目标患者群的筛选,推动晚期恶性肿瘤个体化精准治疗的展开.本文就免疫检查点抑制剂疗效预测生物标志物进行综述,旨在为免疫检查点抑制剂的精准化临床应用提供循证医学依据.方法 应用PubMed和CNKI期刊全文数据库检索系统,以"immunity checkpoint inhibitor,biomark-er,prognosis"为英文关键词,以"免疫检查点抑制剂,疗效,预测"为中文关键词,检索1995-10-2017-02相关文献.纳入标准:(1)免疫检查点抑制剂的定义;(2)免疫检查点抑制剂的作用机制;(3)免疫检查点抑制剂的疗效预测因素.排除标准:(1)研究存在设计缺陷或统计方法错误,质量差;(2)数据不完整,结果不确定.根据纳入及排除标准,共检索到英文文献42篇,中文文献2篇,纳入研究进行分析.结果 免疫检查点抑制剂特异性作用于人体的免疫系统,提高多种免疫细胞的抗肿瘤活性,其整体起效时间慢,但一旦起效,疗效维持时间较长.选择相应的药物疗效预测因子,在用药前筛选出免疫检查点抑制剂治疗的目标人群,对于临床抉择至关重要.PD-L1表达率、微卫星不稳定状态和肿瘤突变负荷等指标已被证明与免疫检查点抑制剂疗效相关.其他新标志物的意义有待进一步研究证实.结论 PD-L1表达率、微卫星不稳定状态和肿瘤突变负荷是目前证据较为充足的免疫检查点抑制剂疗效预测标志物.

Predictive markers of immune checkpoint inhibitors

OBJECTIVE For the past few years,the checkpoint inhibitors,such as PD-1 inhibitors and CTLA-4 in-hibitors,demonstrated an advantage in terms of the survival of melanoma and lung cancer patients with the development of novel immunotherapy agents.Thus,exploring predictive biomarkers may contribute to the screening the target population for immune checkpoint inhibitors and promoting the development of individualized precision therapy in advanced cancer. This article induced the progress about the predictive biomarkers of checkpoint inhibitors,providing a theoretical basis for the precision medicine study of immunotherapy.METHODS Based on Pubmed and CNKI database,by using "immune checkpoint inhibitors,biomarker,prognosis"as key words to trace related papers from 1995-10 to 2017-02.Inclusion crite-ria were as follows:the definition of immune checkpoint inhibitors;the mechanism of immune checkpoint inhibitors;the predictive factors of immune checkpoint inhibitors.Exclusion criteria:(1)Those exists problems in research designs or sta-tistical methods.(2)those has incomplete data or unclear results.Totally 44 papers (2 chinese literatures)were finally in-cluded for analysis.RESULTS The immune checkpoint inhibitors work specifically on the body's immune system to en-hance the antitumor activity of various immune cells.It is relatively slower to take effects.However,once the effects ap-pear,it will last for a very long period.Selecting the appropriate predictive factors and screening the target population be-fore the treatment plays a very important role for clinical choice.It has been proved that the expression rate of PD-L1,mi-crosatellite instability and tumor mutation burden are correlated with the treatment effects of immune checkpoint inhibi-tors.The significance of other biomarkers need further investigation.CONCLUSION The expression rate of PD-L1, microsatellite instability and tumor mutation burden were reliable predictive biomarkers for the treatment effects of im-mune checkpoint inhibitors.