Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Publication date: Available online 12 October 2017
Source:Cell
Author(s): Nadeem Riaz, Jonathan J. Havel, Vladimir Makarov, Alexis Desrichard, Walter J. Urba, 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
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.

Graphical abstract

Teaser

Mutation burden decreases with successful checkpoint blockade therapy in patients with melanoma, suggesting that selection against mutant neoepitopes may be a critical mechanism of action of Nivolumab.


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