title: Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients.
abstract: 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.
authors.affiliation: Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, Connecticut 06520, USA.
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
authors.affiliation: Gustave Roussy South-Paris University, 114 Rue Edouard Vaillant, 94805 Villefuij, Cedex, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Kowanetz
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Gregg D
authors.initials: GD
authors.lastname: Fine
authors.affiliation: The Angeles Clinic and Research Institute, 11818 Wilshire Blvd, Los Angeles, California 90025, USA.
authors.forename: Omid
authors.initials: O
authors.lastname: Hamid
authors.affiliation: Pinnacle Oncology Hematology, 9055 E Del Camino Dr 100, Scottsdale, Arizona 85258, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gordon
authors.affiliation: Vanderbilt-Ingram Cancer Center, 2220 Pierce Avenue, Nashville, Tennessee 37212, USA.
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Sosman
authors.affiliation: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Shapiro 9, Boston, Massachusetts 02215, USA.
authors.forename: David F
authors.initials: DF
authors.lastname: McDermott
authors.affiliation: Carolina BioOncology Institute, 9801 W. Kincey Ave, Suite 145, Huntersville, North Carolina 28078, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Powderly
authors.affiliation: Yale Comprehensive Cancer Center, Yale School of Medicine, 333 Cedar Street, WWW221, New Haven, Connecticut 06520, USA.
authors.forename: Scott N
authors.initials: SN
authors.lastname: Gettinger
authors.affiliation: Stanford University, CCSR Bldg Room 1110, Stanford, California 94305, USA.
authors.forename: Holbrook E K
authors.initials: HE
authors.lastname: Kohrt
authors.affiliation: Vanderbilt-Ingram Cancer Center, 1301 Medical Center Dr, Suite 1710, Nashville, Tennessee 37212, USA.
authors.forename: Leora
authors.initials: L
authors.lastname: Horn
authors.affiliation: Massachusetts General Hospital, 55 Fruit Street, YAW 9E, Boston, Massachusetts 02114, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: Lawrence
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Rost
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Maya
authors.initials: M
authors.lastname: Leabman
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Mokatrin
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Hartmut
authors.initials: H
authors.lastname: Koeppen
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Priti S
authors.initials: PS
authors.lastname: Hegde
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Mellman
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Chen
authors.affiliation: Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: F Stephen
authors.initials: FS
authors.lastname: Hodi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015415:Biomarkers / Q000097:blood; D060908:CTLA-4 Antigen / Q000378:metabolism; D054428:Chemokine CX3CL1 / Q000378:metabolism; D002985:Clinical Protocols; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007167:Immunotherapy / Q000009:adverse effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000175:diagnosis / Q000628:therapy*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D060890:B7-H1 Antigen; D015415:Biomarkers; C423236:CD274 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C000594389:atezolizumab