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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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.
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BMC Immunology (2019)