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Science. 2015 Oct 9;350(6257):207-211. doi: 10.1126/science.aad0095. Epub 2015 Sep 10.

Genomic correlates of response to CTLA-4 blockade in metastatic melanoma.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
2
Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
3
Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
4
Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany.
5
German Cancer Consortium (DKTK), 69121 Heidelberg, Germany.
6
Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.
7
Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland.
8
Skin Cancer Unit, German Cancer Research Center(DKTK), 69121 Heidelberg, Germany.
9
Department of Dermatology, Venerology, and Allergology, University Medical Center, Ruprecht-Karls University of Heidelberg, 68167 Mannheim, Germany.
10
Department of Dermatology, University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany.
11
Department of Dermatology, University Hospital Tübingen, 72076 Tübingen, Germany.
12
Department of Dermatology, University Hospital Kiel, 24105 Kiel, Germany.
13
Department of Dermatology, University Medical Center, 55131 Mainz, Germany.
14
Department of Dermatology, Elbe-Kliniken, 21614 Buxtehude, Germany.
15
Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany.
#
Contributed equally

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.

PMID:
26359337
PMCID:
PMC5054517
DOI:
10.1126/science.aad0095
[Indexed for MEDLINE]
Free PMC Article

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