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    Publication Date: 2015-09-12
    Description: 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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Van Allen, Eliezer M -- Miao, Diana -- Schilling, Bastian -- Shukla, Sachet A -- Blank, Christian -- Zimmer, Lisa -- Sucker, Antje -- Hillen, Uwe -- Foppen, Marnix H Geukes -- Goldinger, Simone M -- Utikal, Jochen -- Hassel, Jessica C -- Weide, Benjamin -- Kaehler, Katharina C -- Loquai, Carmen -- Mohr, Peter -- Gutzmer, Ralf -- Dummer, Reinhard -- Gabriel, Stacey -- Wu, Catherine J -- Schadendorf, Dirk -- Garraway, Levi A -- U54 HG003067/HG/NHGRI NIH HHS/ -- New York, N.Y. -- Science. 2015 Oct 9;350(6257):207-11. doi: 10.1126/science.aad0095. Epub 2015 Sep 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉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. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium(DKTK), 69121 Heidelberg, Germany. ; Department of Medical Oncology, Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands. ; Department of Dermatology, University Hospital Zurich, 8091 Zurich, Switzerland. ; Skin Cancer Unit, German Cancer Research Center(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. ; Department of Dermatology, University Hospital, Ruprecht-Karls University of Heidelberg, 69120 Heidelberg, Germany. ; Department of Dermatology, University Hospital Tubingen, 72076 Tubingen, Germany. ; Department of Dermatology, University Hospital Kiel, 24105 Kiel, Germany. ; Department of Dermatology, University Medical Center, 55131 Mainz, Germany. ; Department of Dermatology, Elbe-Kliniken, 21614 Buxtehude, Germany. ; Department of Dermatology and Allergy, Skin Cancer Center Hannover, Hannover Medical School, 30625 Hannover, Germany. ; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. ; Department of Dermatology, University Hospital, University Duisburg-Essen, 45147 Essen, Germany. German Cancer Consortium(DKTK), 69121 Heidelberg, Germany. levi_garraway@dfci.harvard.edu dirk.schadendorf@uk-essen.de. ; 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. levi_garraway@dfci.harvard.edu dirk.schadendorf@uk-essen.de.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26359337" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Aged ; Aged, 80 and over ; Antibodies, Monoclonal/*pharmacology/therapeutic use ; Antigens, Neoplasm/*genetics ; *Biomarkers, Pharmacological ; CTLA-4 Antigen/*antagonists & inhibitors ; Cell Cycle Checkpoints/genetics/immunology ; Cohort Studies ; DNA Mutational Analysis ; Drug Resistance, Neoplasm/genetics ; Exome ; Female ; Genomics ; HLA Antigens/genetics ; Humans ; Male ; Melanoma/*drug therapy/*genetics/secondary ; Middle Aged ; Mutation ; Skin Neoplasms/*drug therapy/*genetics/pathology ; Tumor Microenvironment/drug effects/immunology ; Young Adult
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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