3 years ago

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab
John-William Sidhom, Timothy A. Chan, Rachna Shah, F. Stephen Hodi, Walter J. Urba, Sviatoslav M. Kendall, Rajarsi Mandal, Jennifer S. Sims, Jonathan J. Havel, Salvador Martín-Algarra, Alexis Desrichard, William H. Sharfman, Nadeem Riaz, Nils Weinhold, Thomas F. Gajewski, Craig L. Slingluff, Christine E. Horak, Luc G.T. Morris, Fengshen Kuo, Diego Chowell, Vladimir Makarov, Han Chang, Wen-Jen Hwu, Shailender Bhatia, Jonathan P. Schneck


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.

Publisher URL: http://www.cell.com/cell/fulltext/S0092-8674(17)31122-4

DOI: 10.1016/j.cell.2017.09.028

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