title: Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.
abstract: Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Miao
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Sachet A
authors.initials: SA
authors.lastname: Shukla
authors.affiliation: Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Blank
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
authors.forename: Lisa
authors.initials: L
authors.lastname: Zimmer
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
authors.forename: Uwe
authors.initials: U
authors.lastname: Hillen
authors.affiliation: Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
authors.forename: Marnix H Geukes
authors.initials: MHG
authors.lastname: Foppen
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Simone M
authors.initials: SM
authors.lastname: Goldinger
authors.affiliation: German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.|Skin Cancer Unit, German Cancer Research Center(DKTK), 69121 Heidelberg, Germany.|Department of Dermatology, Venerology, and Allergology, University Medical Center, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Utikal
authors.affiliation: Department of Dermatology, University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Jessica C
authors.initials: JC
authors.lastname: Hassel
authors.affiliation: Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
authors.affiliation: Department of Dermatology, University Hospital Kiel, 24105 Kiel, Germany.
authors.forename: Katharina C
authors.initials: KC
authors.lastname: Kaehler
authors.affiliation: Department of Dermatology, University Medical Center, 55131 Mainz, Germany.
authors.forename: Carmen
authors.initials: C
authors.lastname: Loquai
authors.affiliation: Department of Dermatology, Elbe-Kliniken, 21614 Buxtehude, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Mohr
authors.affiliation: Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gutzmer
authors.affiliation: Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Stacey
authors.initials: S
authors.lastname: Gabriel
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany.|German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.|Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.|Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000235:genetics*; D054316:Biomarkers, Pharmacological; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D059447:Cell Cycle Checkpoints / Q000235:genetics / Q000276:immunology; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D059472:Exome; D005260:Female; D023281:Genomics; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics* / Q000556:secondary; D008875:Middle Aged; D009154:Mutation; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D054316:Biomarkers, Pharmacological; D060908:CTLA-4 Antigen; D006680:HLA Antigens; D000074324:Ipilimumab