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Nat Med. 2019 Dec;25(12):1916-1927. doi: 10.1038/s41591-019-0654-5. Epub 2019 Dec 2.

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

Author information

1
Dana-Farber Cancer Institute, Boston, MA, USA.
2
Broad Institute of Harvard and MIT, Cambridge, MA, USA.
3
Department of Dermatology, University Hospital Würzburg, Würzburg, Germany.
4
Department of Dermatology, University Hospital, Essen, Germany.
5
German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany.
6
Harvard Medical School, Boston, MA, USA.
7
Skin Cancer Center Hannover, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany.
8
Department of Dermatology, University Medical Center, Mainz, Germany.
9
Biophysics Program, Harvard University, Cambridge, MA, USA.
10
First Department of Medicine, National and Kapodistrian University of Athens, Athens, Greece.
11
Department of Dermatology, University Hospital Zürich, Zürich, Switzerland.
12
Department of Dermatology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany.
13
Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.
14
Department of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
15
Skin Cancer Center at the University Cancer Centre, Department of Dermatology, Faculty of Medicine, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
16
National Center for Tumor Diseases, Dresden, Germany.
17
German Cancer Research Centre, Heidelberg, Germany.
18
Department of Dermatology, Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
19
Medizinische Klinik III, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
20
Department of Dermatology, University Medical Center Tübingen, Tübingen, Germany.
21
Department of Dermatology, University Hospital Regensburg, Regensburg, Germany.
22
Department of Dermatology, University Hospital Berlin, Berlin, Germany.
23
Eli Lilly and Co., Indianapolis, IN, USA.
24
Massachusetts General Hospital, Boston, MA, USA.
25
Dana-Farber Cancer Institute, Boston, MA, USA. eliezerm_vanallen@dfci.harvard.edu.
26
Broad Institute of Harvard and MIT, Cambridge, MA, USA. eliezerm_vanallen@dfci.harvard.edu.
27
Department of Dermatology, University Hospital, Essen, Germany. dirk.schadendorf@uk-essen.de.
28
German Cancer Consortium of Translational Cancer Research, German Cancer Research Center, Heidelberg, Germany. dirk.schadendorf@uk-essen.de.

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.

PMID:
31792460
DOI:
10.1038/s41591-019-0654-5
[Indexed for MEDLINE]
Free PMC Article

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