Document Type

Article

Publication Date

11-2-2017

Publication Title

Cell

Keywords

Antibodies, Monoclonal; Antineoplastic Agents; Genome-Wide Association Study; Humans; Immunotherapy; Melanoma; Nivolumab; Programmed Cell Death 1 Receptor; T-Lymphocytes; Transcriptome; Tumor Microenvironment

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.

Clinical Institute

Cancer

Department

Oncology

Department

Earle A. Chiles Research Institute

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