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|a Liu, David V.
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|a Broad Institute of MIT and Harvard
|e contributor
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|a Liu, Derek
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|a Jerby-Arnon, Livnat
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|a Vokes, Natalie I.
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|a Margolis, Claire A.
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|a Conway, Jake
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|a He, Meng Xiao
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|a Elmarakeby, Haitham
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|a Dietlein, Felix
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|a Miao, Diana
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|a Tracy, Adam
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|a Izar, Benjamin
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|a Regev, Aviv
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|a Van Allen, Eliezer M.
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|a Integrative molecular and clinical modeling of clinical outcomes to PD1 blockade in patients with metastatic melanoma
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|b Springer Science and Business Media LLC,
|c 2020-06-17T18:36:59Z.
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|z Get fulltext
|u https://hdl.handle.net/1721.1/125847
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|a 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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|a Article
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|t 10.1038/s41591-019-0654-5
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|t Nature Medicine
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