Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

被引：1632

作者：

Riaz, Nadeem ^{[1
,2
,3
]}

Havel, Jonathan J. ^{[1
]}

Makarov, Vladimir ^{[1
,3
]}

Desrichard, Alexis ^{[1
]}

Urba, Walter J. ^{[4
]}

Sims, Jennifer S. ^{[1
,3
]}

Hodi, F. Stephen ^{[5
]}

Martin-Algarra, Salvador ^{[6
]}

Mandal, Rajarsi ^{[7
]}

Sharfman, William H. ^{[8
]}

Bhatia, Shailender ^{[9
]}

Hwu, Wen-Jen ^{[10
]}

Gajewski, Thomas F. ^{[11
]}

Slingluff, Craig L., Jr. ^{[12
,13
]}

Chowell, Diego ^{[1
,3
]}

Kendall, Sviatoslav M. ^{[1
,3
]}

Chang, Han ^{[14
]}

Shah, Rachna ^{[1
]}

Kuo, Fengshen ^{[3
]}

Morris, Luc G. T. ^{[3
,7
]}

Sidhom, John-William ^{[15
]}

Schneck, Jonathan P. ^{[15
]}

Horak, Christine E. ^{[14
]}

Weinhold, Nils ^{[2
]}

Chan, Timothy A. ^{[1
,2
,3
]}

机构：

[1] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[2] Mem Sloan Kettering Canc Ctr, Dept Radiat Oncol, New York, NY 10065 USA

[3] Mem Sloan Kettering Canc Ctr, Immunogen & Precis Oncol Platform, New York, NY 10065 USA

[4] Providence Canc Ctr, Earle A Chiles Res Inst, Portland, OR 97213 USA

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

[6] Clin Univ Navarra, Inst Invest Sanitaria Navarra, Med Oncol, Pamplona 31008, Spain

[7] Mem Sloan Kettering Canc Ctr, Dept Surg, New York, NY 10065 USA

[8] Johns Hopkins Univ, Sch Med, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21287 USA

[9] Univ Washington, Fred Hutchinson Canc Res Ctr, Seattle, WA 98105 USA

[10] Univ Texas MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[11] Univ Chicago, Dept Med, Sect Hematol Oncol, 5841 S Maryland Ave, Chicago, IL 60637 USA

[12] Univ Virginia, Sch Med, Dept Surg, Charlottesville, VA 22908 USA

[13] Univ Virginia, Sch Med, Canc Ctr, Charlottesville, VA 22908 USA

[14] Bristol Myers Squibb, Princeton, NJ 08648 USA

[15] Johns Hopkins Univ, Sch Med, Dept Biomed Engn, Baltimore, MD 21205 USA

来源：

CELL | 2017年 / 171卷 / 04期

关键词：

IMMUNE CHECKPOINT BLOCKADE; SOMATIC POINT MUTATIONS; CELL LUNG-CANCER; METASTATIC MELANOMA; PD-1; BLOCKADE; CTLA-4; THERAPY; NEOANTIGENS; EXPRESSION; CARCINOMA;

D O I：

10.1016/j.cell.2017.09.028

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：

The mechanisms by which immune checkpoint blockade modulates tumor evolution during therapy are unclear. We assessed genomic changes in tumors from 68 patients with advanced melanoma, who progressed on ipilimumab or were ipilimumabnaive, before and after nivolumab initiation (CA209-038 study). Tumors were analyzed by whole-exome, transcriptome, and/or T cell receptor (TCR) sequencing. In responding patients, mutation and neoantigen load were reduced from baseline, and analysis of intratumoral heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations on-therapy. Transcriptome analyses before and during nivolumab therapy revealed increases in distinct immune cell subsets, activation of specific transcriptional networks, and upregulation of immune checkpoint genes that were more pronounced in patients with response. Temporal changes in intratumoral TCR repertoire revealed expansion of T cell clones in the setting of neoantigen loss. Comprehensive genomic profiling data in this study provide insight into nivolumab's mechanism of action.

引用

页码：934 / +

页数：21

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