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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 system1,2,3,4. However, tumours are rarely rejected spontaneously, reflecting their ability to maintain an immunosuppressive microenvironment5. 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 killing6,7,8,9,10. The PD-L1–PD-1 axis protects the host from overactive T-effector cells not only in cancer but also during microbial infections11. 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.

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Change history

  • 11 May 2015

    A minor change was made to an amino acid in the Methods.


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We thank the patients and their families. We also thank all of the investigators and their staff, including A. Balmanoukian and P. Boasberg from The Angeles Clinic and Research Institute; T. Powles from Barts Cancer Institute, QMUL, Barts Health NHS Trust; D. Cho from NYU Langone Medical Center; P. Cassier from Centre Léon-Bérard; F. Braiteh from USON Research Network, Comprehensive Cancer Centers of Nevada; N. Vogelzang from USON Research Network, Comprehensive Cancer Centers of Nevada and University of Nevada; T. Choueiri, L. Gandhi, N. Ibrahim and P. Ott from Dana-Farber Cancer Institute; J.-P. Delord and C. Gomez-Rocca from Institut Claudius Regaud; A. Hollebecque and R. Bahleda from Gustave Roussy; L. Emens from Johns Hopkins Medicine, The Sidney Kimmel Comprehensive Cancer Center; K. Flaherty and R. Sullivan from Massachusetts General Hospital; S. Antonia from Moffitt Cancer Center; H. Burris, J. Infante and D. Spigel from Sarah Cannon Research Institute; G. Fisher from Stanford Medicine, Cancer Institute; P. Conkling and L. Garbo from US Oncology Research, Inc.; C. Cruz and J. Tabenero from Vall d’Hebron Institute of Oncology and Vall d’Hebron University Hospital; W. Pao and I. Puzanov from Vanderbilt-Ingram Cancer Center; P. Eder, H. Kluger and M. Sznol from Yale Cancer Center. From Genentech, we thank M. Anderson, M. Boe, Z. Boyd, C. Chappey, M. Denker, R. Desai, L. Fu, B. Irving, D. Jin, W. Kadel, R. Nakamura, I. Rhee, X. Shen, M. Stroh, T. Sumiyoshi, J. Wu, Y. Xin and J. Yi. Support for third-party writing assistance for this manuscript was provided by F. Hoffmann-La Roche Ltd. NCI grants 1R01CA155196 (Battle-2) and P30 CA 016359 (CCSG) to R.S.H. helped support the infrastructure for this trial and program.

Author information


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

    • Roy S. Herbst
    •  & Scott N. Gettinger
  2. Gustave Roussy South-Paris University, 114 Rue Edouard Vaillant, 94805 Villefuij, Cedex, France

    • Jean-Charles Soria
  3. Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA

    • Marcin Kowanetz
    • , Gregg D. Fine
    • , Sandra Rost
    • , Maya Leabman
    • , Yuanyuan Xiao
    • , Ahmad Mokatrin
    • , Hartmut Koeppen
    • , Priti S. Hegde
    • , Ira Mellman
    •  & Daniel S. Chen
  4. The Angeles Clinic and Research Institute, 11818 Wilshire Blvd, Los Angeles, California 90025, USA

    • Omid Hamid
  5. Pinnacle Oncology Hematology, 9055 E Del Camino Dr 100, Scottsdale, Arizona 85258, USA

    • Michael S. Gordon
  6. Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, Tennessee 37212, USA

    • Jeffery A. Sosman
  7. Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Shapiro 9, Boston, Massachusetts 02215, USA

    • David F. McDermott
  8. Carolina BioOncology Institute, 9801 W. Kincey Ave, Suite 145, Huntersville, North Carolina 28078, USA

    • John D. Powderly
  9. Stanford University, CCSR Bldg Room 1110, Stanford, California 94305, USA

    • Holbrook E. K. Kohrt
  10. Vanderbilt-Ingram Cancer Center, 1301 Medical Center Dr, Suite 1710, Nashville, Tennessee 37212, USA

    • Leora Horn
  11. Massachusetts General Hospital, 55 Fruit Street, YAW 9E, Boston, Massachusetts 02114, USA

    • Donald P. Lawrence
  12. Dana-Farber/Brigham and Women’s Cancer Center, 450 Brookline Avenue, Boston, Massachusetts 02215, USA

    • F. Stephen Hodi


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R.S.H., J.-C.S., D.S.C., F.S.H. and J.A.S. contributed to the overall study design. M.K., S.R., Y.X., H.K. and P.S.H. provided the biomarker studies. M.L. performed the pharmacokinetic analysis. I.M. provided the pre-clinical analysis. A.M. performed the statistical analysis. All authors analysed the data. All authors contributed to writing the paper.

Competing interests

R.S.H. is a consultant for and receives research funding from Genentech, Inc. O.H. is a speaker and consultant for, and receives research funding from, Genentech, Inc. F.S.H. works as a non-paid advisor to Genentech, Inc., Bristol-Myers Squibb and Merck; is a member of the Amgen advisory board; is a compensated advisor to Novartis; and received clinical trials support from Genentech, Inc., Bristol-Myers Squibb, Merck and Novartis. L.H. received research funding from Astellas; is a member of advisory boards for Bristol-Myers Squibb, Clovis and Helix BioPharma; provides uncompensated advice for PUMA and Xcovery; is an uncompensated member of Bayer’s steering committee; and received an honoraria from Boehringer Ingelheim. D.F.M. is a participant on advisory boards for Genentech, Inc. Bristol-Myers Squibb and Merck. J.D.P. is the Founder and CEO of Biologics Human Application Lab; worked as a consultant and/or advisor to Bristol-Myers Squibb, Genentech, Inc., Amplimmune and Merck; received honoraria from Bristol-Myers Squibb; received research funding from Bristol-Myers Squibb, Genentech, Inc., Amplimmune, Merck, AstraZeneca and ImClone Systems; and has participated in Bristol-Myers Squibb Speaker’s Bureau and advisory boards. J.-C.S. is a compensated advisory board participant for Genentech, Inc. M.K., G.D.F., S.R., M.L., Y.X., A.M., H.K., P.S.H., I.M. and D.S.C. are employees of Genentech, Inc. M.S.G., J.A.S., S.N.G., H.E.K.K. and D.P.L. have nothing to declare.

Corresponding author

Correspondence to Roy S. Herbst.

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