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Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients

机译：癌症患者对PD-L1抗体MPDL3280A反应的预测相关性

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摘要

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 expres-sing 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 (T_H1) 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.
机译：人类癌症的发展是一个多步骤过程，其特征是驱动或反映肿瘤进展的遗传和表观遗传学改变的积累。这些变化将癌细胞与正常细胞区分开来，从而使肿瘤被免疫系统识别为异物。但是，肿瘤很少自发地被排斥，这反映了它们维持免疫抑制性微环境的能力。在许多癌症和免疫细胞上表达的程序性死亡配体1（PD-L1；也称为B7-H1或CD274），通过结合程序性死亡1（PD- 1）和B7.1（CD80），它们都是T淋巴细胞活化的负调节剂。 PD-L1与其受体的结合可抑制T细胞迁移，细胞毒性介质的增殖和分泌，并限制肿瘤细胞的杀伤力。 PD-L1-PD-1轴不仅在癌症中而且在微生物感染期间均能保护宿主免受过度活跃的T效应细胞的侵害。因此，阻断PD-L1应该可以增强抗癌免疫力，但是对于疗效的预测因素知之甚少。本研究旨在使用工程化人源化抗体MPDL3280A评估PD-L1抑制作用的安全性，活性和生物标志物。在这里，我们表明，在多种癌症类型中，PD-L1水平较高的肿瘤患者中观察到了反应（通过“实体瘤中的反应评估标准”（1.1版）进行评估），尤其是当PD-L1通过肿瘤表达时，浸润的免疫细胞。此外，应答与基线肿瘤标本中的1型T辅助基因（T_H1）基因表达，CTLA4表达和不存在fractalkine（CX3CL1）相关。总之，这些数据表明，MPDL3280A在PD-L1抑制了已有免疫力的患者中最为有效，并且在抗体治疗中得到了重新焕发活力。

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  • 来源
    《Nature》 |2014年第7528期|563-567|共5页
  • 作者

    Roy S. Herbst; Jean-Charles Soria; Marcin Kowanetz; Gregg D. Fine; Omid Hamid; Michael S. Gordon; Jeffery A. Sosman; David F. McDermott; John D. Powderly; Scott N. Gettinger; Holbrook E. K. Kohrt; Leora Horn; Donald P. Lawrence; Sandra Rost; Maya Leabman; Yuanyuan Xiao; Ahmad Mokatrin; Hartmut Koeppen; Priti S. Hegde; Ira Mellman; Daniel S. Chen; F. Stephen Hodi;

  • 作者单位

    Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, Connecticut 06520, USA;

    Gustave Roussy South-Paris University, 114 Rue Edouard Vaillant, 94805 Villefuij, Cedex, France;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    The Angeles Clinic and Research Institute, 11818 Wilshire Blvd. Los Angeles, California 90025, USA;

    Pinnacle Oncology Hematology, 9055 E Del Camino 100, Scottsdale, Arizona 85258, USA;

    Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, Tennessee 37212, USA;

    Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Shapiro 9, Boston, Massachusetts 02215, USA;

    Carolina BioOncology Institute,9801 W. Kincey Ave, Suite 145,Huntersville, North Carolina 28078, USA;

    Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, Connecticut 06520, USA;

    Stanford University, CCSR Bldg Room 1110, Stanford, California 94305, USA;

    Vanderbilt-Ingram Cancer Center, 1301 Medical Center Suite 1710, Nashville,Tennessee 37212, USA;

    Massachusetts General Hospital, 55 Fruit Street, YAW 9E, Boston, Massachusetts 02114, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA;

    Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, Massachusetts 02215, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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