Tumor and Microenvironment Evolution during Immunotherapy with Nivolumab

Abstract

SUMMARY 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 mechanism of action.

Nivolumab as first-line treatment in non-small cell lung cancer patients—key factors: tumor mutation burden and PD-L1 ≥50%

“…A high frequency of patients switching from chemotherapy to nivolumab in Editorial Nivolumab as first-line treatment in non-small cell lung cancer patients-key factors: tumor mutation burden and PD-L1 ≥50% Patients characteristics were in favor of the chemotherapy group (e.g., fewer liver metastasis, smaller tumor burden and higher proportion of women). It has been previously observed that patients with PD-L1 >50% and high tumor burden benefit from nivolumab administration, however; the number of patients with these characteristics were fewer in the nivolumab group (14). In this study, it was observed that tumor mutation burden on its own is a key factor for nivolumab efficacy and longer median progression free survival.…”

Complex interplay between tumor microenvironment and cancer therapy

“…clones in the TME in the setting of neoantigen loss [129]. The study demonstrates a dramatic remodeling upon anti-PD-1 therapy and provides insight into the mechanism of action.…”

“…In one of the recent studies, the authors performed extensive immunogenomic analyses on melanoma samples treated with anti-PD-1 therapy. 68 patients with advanced melanoma, whose diseases progressed on anti-CTLA-4 therapy or were anti-CTLA-4 therapy naïve were employed to characterize how tumor genomic and TME features changed over time after anti-PD-1 therapy [129]. The authors found that mutation and neoantigen load were reduced from baseline in TME among patients who were responding to the therapy [129].…”

“…68 patients with advanced melanoma, whose diseases progressed on anti-CTLA-4 therapy or were anti-CTLA-4 therapy naïve were employed to characterize how tumor genomic and TME features changed over time after anti-PD-1 therapy [129]. The authors found that mutation and neoantigen load were reduced from baseline in TME among patients who were responding to the therapy [129]. Analysis of TME heterogeneity during therapy demonstrated differential clonal evolution within tumors and putative selection against neoantigenic mutations.…”

Trial watch: Peptide-based vaccines in anticancer therapy

“…1-7 Over the past years, a panoply of different approaches has been developed or repurposed to (re)initiate anticancer immunity, 8-12 including immune checkpoint blockers targeting cytotoxic T lymphocyte-associated protein 4 (CTLA4), programmed cell death 1 (PDCD1, best known as PD-1) and its main ligand CD274 (best known as PD-L1); 13-19 chemotherapy with immunogenic cell death (ICD) inducers, 20-25 recombinant cytokines, 26,27 monoclonal antibodies (mAbs) that activate co-activatory receptors, 28,29 adoptively transferred T cells engineered to express a tumor-specific chimeric antigen receptor (CAR), 30-36 as well as multiple small molecules targeting distinct immunosuppressive pathways operating within the tumor microenvironment. 37-40 Although some of these strategies have demonstrated unprecedented activity in patients with advanced tumors refractory to several lines of conventional treatment, 41 the fraction of individuals responding to single-agent immunotherapy is generally low, 42-45 arguably with the sole exception of CAR-expressing T cells, which have been associated with >70% overall response rate in pediatric patients with B-cell acute lymphocytic leukemia (ALL).…”