Genomic correlates of response to CTLA-4 blockade in metastatic melanoma

被引：2193

作者：

Van Allen, Eliezer M. ^{[1
,2
,3
]}

Miao, Diana ^{[1
,2
]}

Schilling, Bastian ^{[4
,5
]}

Shukla, Sachet A. ^{[1
,2
]}

Blank, Christian ^{[6
]}

Zimmer, Lisa ^{[4
,5
]}

Sucker, Antje ^{[4
,5
]}

Hillen, Uwe ^{[4
,5
]}

Foppen, Marnix H. Geukes ^{[6
]}

Goldinger, Simone M. ^{[7
]}

Utikal, Jochen ^{[5
,8
,9
]}

Hassel, Jessica C. ^{[10
]}

Weide, Benjamin ^{[11
]}

Kaehler, Katharina C. ^{[12
]}

Loquai, Carmen ^{[13
]}

Mohr, Peter ^{[14
]}

Gutzmer, Ralf ^{[15
]}

Dummer, Reinhard ^{[7
]}

Gabriel, Stacey ^{[2
]}

Wu, Catherine J. ^{[1
,2
]}

Schadendorf, Dirk ^{[4
,5
]}

Garraway, Levi A. ^{[1
,2
,3
]}

机构：

[1] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

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

[3] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA

[4] Univ Duisburg Essen, Univ Hosp, Dept Dermatol, D-45147 Essen, Germany

[5] German Canc Consortium DKTK, D-69121 Heidelberg, Germany

[6] Netherlands Canc Inst, Dept Med Oncol, NL-1066 CX Amsterdam, Netherlands

[7] Univ Zurich Hosp, Dept Dermatol, CH-8091 Zurich, Switzerland

[8] German Canc Res Ctr, Skin Canc Unit, D-69121 Heidelberg, Germany

[9] Heidelberg Univ, Univ Med Ctr, Dept Dermatol Venerol & Allergol, D-68167 Mannheim, Germany

[10] Heidelberg Univ, Univ Hosp, Dept Dermatol, D-69120 Heidelberg, Germany

[11] Univ Hosp Tubingen, Dept Dermatol, D-72076 Tubingen, Germany

[12] Univ Hosp Kiel, Dept Dermatol, D-24105 Kiel, Germany

[13] Univ Med Ctr Mainz, Dept Dermatol, D-55131 Mainz, Germany

[14] Elbe Kliniken, Dept Dermatol, D-21614 Buxtehude, Germany

[15] Hannover Med Sch, Skin Canc Ctr Hannover, Dept Dermatol & Allergy, D-30625 Hannover, Germany

来源：

SCIENCE | 2015年 / 350卷 / 6257期

关键词：

IPILIMUMAB PLUS DACARBAZINE; PD-1; BLOCKADE; NEO-ANTIGENS; MUTATIONS; TUMORS; SURVIVAL; LANDSCAPE; NIVOLUMAB; SAMPLES;

D O I：

10.1126/science.aad0095

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Monoclonal antibodies directed against cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), such as ipilimumab, yield considerable clinical benefit for patients with metastatic melanoma by inhibiting immune checkpoint activity, but clinical predictors of response to these therapies remain incompletely characterized. To investigate the roles of tumor-specific neoantigens and alterations in the tumor microenvironment in the response to ipilimumab, we analyzed whole exomes from pretreatment melanoma tumor biopsies and matching germline tissue samples from 110 patients. For 40 of these patients, we also obtained and analyzed transcriptome data from the pretreatment tumor samples. Overall mutational load, neoantigen load, and expression of cytolytic markers in the immune microenvironment were significantly associated with clinical benefit. However, no recurrent neoantigen peptide sequences predicted responder patient populations. Thus, detailed integrated molecular characterization of large patient cohorts may be needed to identify robust determinants of response and resistance to immune checkpoint inhibitors.

引用

页码：207 / 211

页数：5

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