Nivolumab Induces Tumor Evolution in Patients with Melanoma

Immune checkpoint blockade agents, including the anti–PD-1 antibody nivolumab and the anti-CTLA4 antibody ipilimumab, extend survival in a subset of patients with multiple tumor types. However, it is not clear how anti–PD-1 therapy affects the tumor mutational landscape and microenvironment. To address this question, Riaz, Havel, Makarov, and colleagues performed whole-exome, transcriptome, and/or T-cell receptor (TCR) sequencing of tumors from 68 patients with advanced melanoma (35 of whom had previously progressed on ipilimumab) before and after nivolumab initiation. In ipilimumab-naïve patients, a high tumor mutation load was associated with increased overall survival after nivolumab treatment, but no single gene mutations were associated with increased response or resistance to nivolumab. Further, whole-exome sequencing in pre- and post-nivolumab samples from 41 patients revealed that nivolumab treatment reduced mutation and neoantigen load in responding patients, suggesting that nivolumab induces tumor evolution by selecting against select neoantigens. Consistent with these findings, nearly all responding patients exhibited loss of one or more clones on-therapy, whereas patients with stable or progressive disease often gained novel sets of mutations. Transcriptome analysis showed that responders who had progressed on ipilimumab had an immunologically active environment, in contrast to ipilimumab-naïve responders who exhibited variable immunologic activity. Further, nivolumab treatment resulted in feedback, increasing expression of a number of immune checkpoint genes in responders and nonresponders. Response to nivolumab was associated with an increase in CD8⁺ T cells and natural killer cells, and a decrease in M1 macrophages. Nivolumab also induced shifts in the TCR repertoire, with T-cell clone expansion occurring with neoantigen loss. Collectively, the comprehensive genomic profiling of melanomas on nivolumab therapy extends the understanding of the mechanism of action of checkpoint inhibitors and demonstrates that nivolumab induces tumor clonal evolution by selecting against mutant neoepitopes.

Riaz N, Havel JJ, Makarov V, Desrichard A, Urba WJ, Sims JS, et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 2017 Oct 11 [Epub ahead of print].

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