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 2

Nivolumab and ipilimumab differentially impact on peripheral blood immunophenotypes.

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Nivolumab and ipilimumab differentially impact on peripheral blood immun...
(A) The median frequency at baseline on the x axis and the week-13 median frequency on the y axis is shown for significantly changed immunophenotypes (P < 0.05, Wilcoxon signed-rank test) in nivolumab-treated patient samples. Each dot represents an immunophenotype and is colored by P value. The purple dotted line with a slope of 1 corresponds to no change in median frequency. (B) Ipilimumab-treated patient samples are likewise shown. (C) A Venn diagram is shown with the number of significantly changed immunophenotypes in each group and the overlap. The 525 immunophenotypes are those overlapping with changes in the same direction in both NIVO- and IPI-treated patient samples. (D) The median relative change from baseline to week 13 in nivolumab-treated patient samples on the x axis and the relative change in ipilimumab-treated patient samples on the y axis is shown for the 584 overlapping immunophenotypes. The purple dotted lines correspond to no change in median frequency. (E) The delta values (week 13 minus baseline) of the 584 overlapping phenotypes were used in an elastic net regularized regression model to categorize whether a paired patient sample received nivolumab or ipilimumab treatment. The receiver operator characteristic (ROC) and resulting AUC for all paired samples is shown by the dotted black line in the left panel. The ROC and AUC for responding patient samples is shown in blue and for progressing patient samples in red. The model values for nivolumab and ipilimumab-treated paired patient samples are plotted in the right panel. Box plots show median ± quartiles with whiskers indicating range.