Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • David Liu - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Bastian Schilling - , University of Würzburg, University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)
  • Derek Liu - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT, Harvard University (Author)
  • Antje Sucker - , University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)
  • Elisabeth Livingstone - , University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)
  • Livnat Jerby-Amon - , Broad Institute of Harvard University and MIT (Author)
  • Lisa Zimmer - , University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)
  • Ralf Gutzmer - , Hannover Medical School (MHH) (Author)
  • Imke Satzger - , Hannover Medical School (MHH) (Author)
  • Carmen Loquai - , Johannes Gutenberg University Mainz (Author)
  • Stephan Grabbe - , Johannes Gutenberg University Mainz (Author)
  • Natalie Vokes - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Claire A. Margolis - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Jake Conway - , Broad Institute of Harvard University and MIT, Harvard University (Author)
  • Meng Xiao He - , Broad Institute of Harvard University and MIT, Harvard University (Author)
  • Haitham Elmarakeby - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Felix Dietlein - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Diana Miao - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT, Harvard University (Author)
  • Adam Tracy - , Broad Institute of Harvard University and MIT (Author)
  • Helen Gogas - , National and Kapodistrian University of Athens (Author)
  • Simone M. Goldinger - , University of Zurich (Author)
  • Jochen Utikal - , Heidelberg University , German Cancer Research Center (DKFZ) (Author)
  • Christian U. Blank - , Netherlands Cancer Institute (Author)
  • Ricarda Rauschenberg - , Department of Dermatology, National Center for Tumor Diseases Dresden, University Hospital Carl Gustav Carus Dresden, German Cancer Research Center (DKFZ) (Author)
  • Dagmar von Bubnoff - , University Medical Center Freiburg (Author)
  • Angela Krackhardt - , German Cancer Research Center (DKFZ), Technical University of Munich (Author)
  • Benjamin Weide - , University Hospital Tübingen (Author)
  • Sebastian Haferkamp - , University of Regensburg (Author)
  • Felix Kiecker - , Charité – Universitätsmedizin Berlin (Author)
  • Ben Izar - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Levi Garraway - , Eli Lilly (Author)
  • Aviv Regev - , Broad Institute of Harvard University and MIT (Author)
  • Keith Flaherty - , Harvard University (Author)
  • Annette Paschen - , University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)
  • Eliezer M. Van Allen - , Dana-Farber Cancer Institute, Broad Institute of Harvard University and MIT (Author)
  • Dirk Schadendorf - , University of Duisburg-Essen, German Cancer Research Center (DKFZ) (Author)

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.

Details

Original languageEnglish
Pages (from-to)1916-1927
Number of pages12
JournalNature medicine
Volume25
Issue number12
Publication statusPublished - 1 Dec 2019
Peer-reviewedYes

External IDs

PubMed 31792460
ORCID /0009-0001-4054-4024/work/155291690

Keywords