Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.

Abstract:

: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 ipilimumab-naive, 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.

journal_name

Cell

journal_title

Cell

authors

Riaz N,Havel JJ,Makarov V,Desrichard A,Urba WJ,Sims JS,Hodi FS,Martín-Algarra S,Mandal R,Sharfman WH,Bhatia S,Hwu WJ,Gajewski TF,Slingluff CL Jr,Chowell D,Kendall SM,Chang H,Shah R,Kuo F,Morris LGT,Sidhom JW,Sch

doi

10.1016/j.cell.2017.09.028

subject

Has Abstract

pub_date

2017-11-02 00:00:00

pages

934-949.e16

issue

4

eissn

0092-8674

issn

1097-4172

pii

S0092-8674(17)31122-4

journal_volume

171

pub_type

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