Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
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DOI：
10.1038/nature14011
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发表时间：
2014-11-27
期刊：
影响因子：
64.8
通讯作者：
Hodi FS
中科院分区：
文献类型：
--
作者：
Herbst RS;Soria JC;Kowanetz M;Fine GD;Hamid O;Gordon MS;Sosman JA;McDermott DF;Powderly JD;Gettinger SN;Kohrt HE;Horn L;Lawrence DP;Rost S;Leabman M;Xiao Y;Mokatrin A;Koeppen H;Hegde PS;Mellman I;Chen DS;Hodi FS
人类癌症的发展是一个多步骤的过程，其特征是驱动或反映肿瘤进展的遗传和表观遗传改变的积累。这些变化将癌细胞与正常细胞区分开来，使肿瘤被免疫系统识别为外来物。然而，肿瘤很少自发地被排斥，这反映了它们维持免疫抑制微环境的能力。程序性死亡配体1（PD-L1;也称为B7-H1或CD 274）在许多癌症和免疫细胞上表达，通过结合程序性死亡-1（PD-1）和B7.1（CD 80）在阻断“癌症免疫周期”中发挥重要作用，两者都是T淋巴细胞活化的负调节因子。PD-L1与其受体的结合抑制T细胞迁移、增殖和细胞毒性介质的分泌，并限制肿瘤细胞杀伤，。PD-L1-PD-1轴不仅在癌症中而且在微生物感染期间保护宿主免受过度活跃的T效应细胞的影响。因此，阻断PD-L1应该会增强抗癌免疫力，但对疗效的预测因素知之甚少。本研究旨在评价使用工程化人源化抗体MPDL 3280 A抑制PD-L1的安全性、活性和生物标志物。在这里，我们表明，在多种癌症类型中，在表达高水平PD-L1的肿瘤患者中观察到缓解（根据实体瘤缓解评价标准，第1.1版评价），特别是当PD-L1由肿瘤浸润免疫细胞表达时。此外，在基线肿瘤标本中，应答与1型辅助性T细胞（TH 1）基因表达、CTLA 4表达和不存在fractalkine（CX 3CL 1）相关。总之，这些数据表明，MPDL 3280 A在预先存在的免疫力被PD-L1抑制的患者中最有效，并且在抗体治疗后恢复。
The development of human cancer is a multistep process characterized by the accumulation of genetic and epigenetic alterations that drive or reflect tumour progression. These changes distinguish cancer cells from their normal counterparts, allowing tumours to be recognized as foreign by the immune system,,,. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment. Programmed death-ligand 1 (PD-L1; also called B7-H1 or CD274), which is expressed on many cancer and immune cells, plays an important part in blocking the ‘cancer immunity cycle’ by binding programmed death-1 (PD-1) and B7.1 (CD80), both of which are negative regulators of T-lymphocyte activation. Binding of PD-L1 to its receptors suppresses T-cell migration, proliferation and secretion of cytotoxic mediators, and restricts tumour cell killing,,,,. The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections. Blocking PD-L1 should therefore enhance anticancer immunity, but little is known about predictive factors of efficacy. This study was designed to evaluate the safety, activity and biomarkers of PD-L1 inhibition using the engineered humanized antibody MPDL3280A. Here we show that across multiple cancer types, responses (as evaluated by Response Evaluation Criteria in Solid Tumours, version 1.1) were observed in patients with tumours expressing high levels of PD-L1, especially when PD-L1 was expressed by tumour-infiltrating immune cells. Furthermore, responses were associated with T-helper type 1 (TH1) gene expression, CTLA4 expression and the absence of fractalkine (CX3CL1) in baseline tumour specimens. Together, these data suggest that MPDL3280A is most effective in patients in which pre-existing immunity is suppressed by PD-L1, and is re-invigorated on antibody treatment.