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Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab.
  • Nadeem Riaz
  • Jonathan J Havel
  • Vladimir Makarov
  • Alexis Desrichard
  • Walter Urba, Earle A. Chiles Research Institute, Providence Cancer Center, Portland, OR, 97213, USA.
  • Jennifer S Sims
  • F Stephen Hodi
  • Salvador Martín-Algarra
  • Rajarsi Mandal
  • William H Sharfman
  • Shailender Bhatia
  • Wen-Jen Hwu
  • Thomas F Gajewski
  • Craig L Slingluff
  • Diego Chowell
  • Sviatoslav M Kendall
  • Han Chang
  • Rachna Shah
  • Fengshen Kuo
  • Luc G T Morris
  • John-William Sidhom
  • Jonathan P Schneck
  • Christine E Horak
  • Nils Weinhold
  • Timothy A Chan
Document Type
Publication Date
  • Antibodies, Monoclonal,
  • Antineoplastic Agents,
  • Genome-Wide Association Study,
  • Humans,
  • Immunotherapy,
  • Melanoma,
  • Nivolumab,
  • Programmed Cell Death 1 Receptor,
  • T-Lymphocytes,
  • Transcriptome,
  • Tumor Microenvironment

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
Earle A. Chiles Research Institute
Citation Information
Nadeem Riaz, Jonathan J Havel, Vladimir Makarov, Alexis Desrichard, et al.. "Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab." Cell (2017)
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