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

被引：666

作者：

Liu, David ^{[1
,2
]}

Schilling, Bastian ^{[3
,4
,5
]}

Liu, Derek ^{[1
,2
,6
]}

Sucker, Antje ^{[4
,5
]}

Livingstone, Elisabeth ^{[4
,5
]}

Jerby-Amon, Livnat ^{[2
]}

Zimmer, Lisa ^{[4
,5
]}

Gutzmer, Ralf ^{[7
]}

Satzger, Imke ^{[7
]}

Loquai, Carmen ^{[8
]}

Grabbe, Stephan ^{[8
]}

Vokes, Natalie ^{[1
,2
]}

Margolis, Claire A. ^{[1
,2
]}

Conway, Jake ^{[2
,6
]}

He, Meng Xiao ^{[2
,6
,9
]}

Elmarakeby, Haitham ^{[1
,2
]}

Dietlein, Felix ^{[1
,2
]}

Miao, Diana ^{[1
,2
,6
]}

Tracy, Adam ^{[2
]}

Gogas, Helen ^{[10
]}

Goldinger, Simone M. ^{[11
]}

Utikal, Jochen ^{[12
,13
]}

Blank, Christian U. ^{[14
]}

Rauschenberg, Ricarda ^{[15
,16
,17
]}

von Bubnoff, Dagmar ^{[18
]}

Krackhardt, Angela ^{[5
,19
]}

Weide, Benjamin ^{[20
]}

Haferkamp, Sebastian ^{[21
]}

Kiecker, Felix ^{[22
]}

Izar, Ben ^{[1
,2
]}

Garraway, Levi ^{[23
]}

Regev, Aviv ^{[2
]}

Flaherty, Keith ^{[24
]}

Paschen, Annette ^{[4
,5
]}

Van Allen, Eliezer M. ^{[1
,2
]}

Schadendorf, Dirk ^{[4
,5
]}

机构：

[1] Dana Farber Canc Inst, Boston, MA 02115 USA

[2] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[3] Univ Hosp Wurzburg, Dept Dermatol, Wurzburg, Germany

[4] Univ Hosp, Dept Dermatol, Essen, Germany

[5] German Canc Res Ctr, German Canc Consortium Translat Canc Res, Heidelberg, Germany

[6] Harvard Med Sch, Boston, MA 02115 USA

[7] Hannover Med Sch, Dept Dermatol & Allergy, Skin Canc Ctr Hannover, Hannover, Germany

[8] Univ Med Ctr, Dept Dermatol, Mainz, Germany

[9] Harvard Univ, Biophys Program, Cambridge, MA 02138 USA

[10] Natl & Kapodistrian Univ Athens, Dept Med 1, Athens, Greece

[11] Univ Hosp Zurich, Dept Dermatol, Zurich, Switzerland

[12] Ruprecht Karl Univ Heidelberg, Univ Med Ctr Mannheim, Dept Dermatol, Mannheim, Germany

[13] German Canc Res Ctr, Skin Canc Unit, Heidelberg, Germany

[14] Netherlands Canc Inst, Dept Med Oncol, Amsterdam, Netherlands

[15] Tech Univ Dresden, Univ Hosp Carl Gustav Carus, Fac Med, Skin Canc Ctr,Univ Canc Ctr,Dept Dermatol, Dresden, Germany

[16] Natl Ctr Tumor Dis, Dresden, Germany

[17] German Canc Res Ctr, Heidelberg, Germany

[18] Univ Freiburg, Fac Med, Med Ctr, Dept Dermatol, Freiburg, Germany

[19] Tech Univ Munich, Klinikum Rechts Isar, Med Klin 3, Munich, Germany

[20] Univ Med Ctr Tubingen, Dept Dermatol, Tubingen, Germany

[21] Univ Hosp Regensburg, Dept Dermatol, Regensburg, Germany

[22] Univ Hosp Berlin, Dept Dermatol, Berlin, Germany

[23] Eli Lilly & Co, Indianapolis, IN 46285 USA

[24] Massachusetts Gen Hosp, Boston, MA 02114 USA

来源：

NATURE MEDICINE | 2019年 / 25卷 / 12期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

PD-1; BLOCKADE; OPEN-LABEL; CTLA-4; RESISTANCE; MUTATIONS; PEMBROLIZUMAB; IPILIMUMAB; SIGNATURES; NIVOLUMAB; MULTICENTER;

D O I：

10.1038/s41591-019-0654-5

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：1916 / +

页数：26

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