Riaz et al. examined the effects of 4 weeks of nivolumab therapy in ipilimumab (IPI)-naïve or -progressor patients stratified according to good or poor response to nivolumab. In responding patients, mutation and neoantigen load contracted, presumably due to therapy-induced immunoediting, and the intratumoral TCR repertoire expanded in number (IPI-progressors) or became more unequally distributed (IPI-naïve), suggesting antigen-driven changes in the T cell population.
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.