Nivolumab and ipilimumab are associated with distinct immune landscape changes and response-associated immunophenotypes
David M. Woods, Andressa S. Laino, Aidan Winters, Jason Alexandre, Daniel Freeman, Vinay Rao, Santi S. Adavani, Jeffery S. Weber, Pratip K. Chattopadhyay
David M. Woods, Andressa S. Laino, Aidan Winters, Jason Alexandre, Daniel Freeman, Vinay Rao, Santi S. Adavani, Jeffery S. Weber, Pratip K. Chattopadhyay
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Clinical Research and Public Health Immunology Oncology

Nivolumab and ipilimumab are associated with distinct immune landscape changes and response-associated immunophenotypes

Abstract

BACKGROUND The reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well described.METHODS We used high-parameter flow cytometry and a computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO > IPI or IPI > NIVO (Checkmate-064).RESULTS The 2 treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response. Only 2 immunophenotypes were shared but had opposing relationships to response/survival. To understand the impact of sequential treatment on response/survival, phenotypes that changed after the initial treatment and differentiated response in the other cohort were identified. Immunophenotypic changes occurring after NIVO were predominately associated with response to IPI > NIVO, but changes occurring after IPI were predominately associated with progression after NIVO > IPI. Among these changes, CD4+CD38+CD39+CD127–GARP– T cell subsets were increased after IPI treatment and were negatively associated with response/survival for the NIVO > IPI cohort.CONCLUSION Collectively, these data suggest that the impact of IPI and NIVO on the immunophenotypic landscape of patients is distinct and that the impact of IPI may be associated with resistance to subsequent NIVO therapy, consistent with poor outcomes in the IPI > NIVO cohort of Checkmate-064.

Authors

David M. Woods, Andressa S. Laino, Aidan Winters, Jason Alexandre, Daniel Freeman, Vinay Rao, Santi S. Adavani, Jeffery S. Weber, Pratip K. Chattopadhyay

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Figure 5

Ipilimumab-induced immunophenotypic changes are associated with lack of response to sequential nivolumab > ipilimumab.

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Ipilimumab-induced immunophenotypic changes are associated with lack of ...
(A) A representative immunophenotype increased after nivolumab and having an increased frequency in responding patients is shown. The left-most graph shows the paired frequency changes in nivolumab-treated patients (significance determined using Wilcoxon signed-rank test). Responding patients are represented by blue lines, nonresponding patients with red lines, and nonevaluable patients in black. The second to left graph plots the week-13, postipilimumab frequencies of this population comparing responding and nonresponding patients. Box plots show median ± quartiles, with whiskers indicating range. Significance was determined by Mann-Whitney U test. The third panel is a survival plot for this immunophenotype. Patients were stratified based on median frequency of the immunophenotype at week 13. Patients with greater than median frequencies are shown in orange and less than median frequency in green. Significance was determined by Mantel-Cox test. The right-most graph shows the paired frequency changes in an independent validation cohort of nivolumab-treated patients. Significance was determined by Mann-Whitney U test. (B) A representative immunophenotype increasing after ipilimumab and having decreased frequency at baseline in nivolumab > ipilimumab responding patients is likewise shown. (C) A representative immunophenotype decreasing after ipilimumab and having increased frequency at baseline in nivolumab > ipilimumab responding patients is likewise shown.