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Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma.
Liu, David; Schilling, Bastian; Liu, Derek; Sucker, Antje; Livingstone, Elisabeth; Jerby-Arnon, Livnat; Zimmer, Lisa; Gutzmer, Ralf; Satzger, Imke; Loquai, Carmen; Grabbe, Stephan; Vokes, Natalie; Margolis, Claire A; Conway, Jake; He, Meng Xiao; Elmarakeby, Haitham; Dietlein, Felix; Miao, Diana; Tracy, Adam; Gogas, Helen; Goldinger, Simone M; Utikal, Jochen; Blank, Christian U; Rauschenberg, Ricarda; von Bubnoff, Dagmar; Krackhardt, Angela; Weide, Benjamin; Haferkamp, Sebastian; Kiecker, Felix; Izar, Ben; Garraway, Levi; Regev, Aviv; Flaherty, Keith; Paschen, Annette; Van Allen, Eliezer M; Schadendorf, Dirk.
Affiliation
  • Liu D; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Schilling B; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Liu D; Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
  • Sucker A; Department of Dermatology, University Hospital, Essen, Germany.
  • Livingstone E; German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
  • Jerby-Arnon L; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Zimmer L; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Gutzmer R; Harvard Medical School, Boston, MA, USA.
  • Satzger I; Department of Dermatology, University Hospital, Essen, Germany.
  • Loquai C; German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
  • Grabbe S; Department of Dermatology, University Hospital, Essen, Germany.
  • Vokes N; German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
  • Margolis CA; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Conway J; Department of Dermatology, University Hospital, Essen, Germany.
  • He MX; German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
  • Elmarakeby H; Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
  • Dietlein F; Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
  • Miao D; Department of Dermatology, University Medical Center, Mainz, Germany.
  • Tracy A; Department of Dermatology, University Medical Center, Mainz, Germany.
  • Gogas H; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Goldinger SM; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Utikal J; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Blank CU; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Rauschenberg R; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • von Bubnoff D; Harvard Medical School, Boston, MA, USA.
  • Krackhardt A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Weide B; Harvard Medical School, Boston, MA, USA.
  • Haferkamp S; Biophysics Program, Harvard University, Cambridge, MA, USA.
  • Kiecker F; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Izar B; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Garraway L; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Regev A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Flaherty K; Dana-Farber Cancer Institute, Boston, MA, USA.
  • Paschen A; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
  • Van Allen EM; Harvard Medical School, Boston, MA, USA.
  • Schadendorf D; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
Nat Med ; 25(12): 1916-1927, 2019 12.
Article in En | MEDLINE | ID: mdl-31792460
ABSTRACT
Immune-checkpoint blockade (ICB) has demonstrated efficacy in many tumor types, but predictors of responsiveness to anti-PD1 ICB are incompletely characterized. In this study, we analyzed a clinically annotated cohort of patients with melanoma (n = 144) treated with anti-PD1 ICB, with whole-exome and whole-transcriptome sequencing of pre-treatment tumors. We found that tumor mutational burden as a predictor of response was confounded by melanoma subtype, whereas multiple novel genomic and transcriptomic features predicted selective response, including features associated with MHC-I and MHC-II antigen presentation. Furthermore, previous anti-CTLA4 ICB exposure was associated with different predictors of response compared to tumors that were naive to ICB, suggesting selective immune effects of previous exposure to anti-CTLA4 ICB. Finally, we developed parsimonious models integrating clinical, genomic and transcriptomic features to predict intrinsic resistance to anti-PD1 ICB in individual tumors, with validation in smaller independent cohorts limited by the availability of comprehensive data. Broadly, we present a framework to discover predictive features and build models of ICB therapeutic response.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CTLA-4 Antigen / Programmed Cell Death 1 Receptor / Melanoma Type of study: Prognostic_studies Limits: Female / Humans / Male Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2019 Type: Article Affiliation country: United States
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: CTLA-4 Antigen / Programmed Cell Death 1 Receptor / Melanoma Type of study: Prognostic_studies Limits: Female / Humans / Male Language: En Journal: Nat Med Journal subject: BIOLOGIA MOLECULAR / MEDICINA Year: 2019 Type: Article Affiliation country: United States