TY - JOUR
T1 - Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
AU - Liu, David
AU - Schilling, Bastian
AU - Liu, Derek
AU - Sucker, Antje
AU - Livingstone, Elisabeth
AU - Jerby-Amon, Livnat
AU - Zimmer, Lisa
AU - Gutzmer, Ralf
AU - Satzger, Imke
AU - Loquai, Carmen
AU - Grabbe, Stephan
AU - Vokes, Natalie
AU - Margolis, Claire A.
AU - Conway, Jake
AU - He, Meng Xiao
AU - Elmarakeby, Haitham
AU - Dietlein, Felix
AU - Miao, Diana
AU - Tracy, Adam
AU - Gogas, Helen
AU - Goldinger, Simone M.
AU - Utikal, Jochen
AU - Blank, Christian U.
AU - Rauschenberg, Ricarda
AU - von Bubnoff, Dagmar
AU - Krackhardt, Angela
AU - Weide, Benjamin
AU - Haferkamp, Sebastian
AU - Kiecker, Felix
AU - Izar, Ben
AU - Garraway, Levi
AU - Regev, Aviv
AU - Flaherty, Keith
AU - Paschen, Annette
AU - Van Allen, Eliezer M.
AU - Schadendorf, Dirk
N1 - Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85075928991&partnerID=8YFLogxK
U2 - 10.1038/s41591-019-0654-5
DO - 10.1038/s41591-019-0654-5
M3 - Journal articles
C2 - 31792460
AN - SCOPUS:85075928991
SN - 1078-8956
VL - 25
SP - 1916
EP - 1927
JO - Nature Medicine
JF - Nature Medicine
IS - 12
ER -
