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
View: Text | PDF
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

×

Figure 4

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

Options: View larger image (or click on image) Download as PowerPoint
Ipilimumab-induced immunophenotypic changes are associated with lack of ...
(A) A Venn diagram is shown with the number of immunophenotypes significantly changed after nivolumab (purple circle) and immunophenotypes significantly different for survival and response in ipilimumab > nivolumab–treated patients at baseline (top orange circle) and after ipilimumab (bottom orange circle). The direction of change and relative representation in responding patients for overlapping immunophenotypes at baseline (top quadrant plot) and after ipilimumab (bottom quadrant plot) is plotted. The number of immunophenotypes significantly increased after nivolumab and lower in ipilimumab-nivolumab responding patients are shown in the top left quadrants. The number of immunophenotypes significantly increased after nivolumab and higher in ipilimumab > nivolumab responding patients are shown in the top right quadrants. The number of immunophenotypes significantly decreased after nivolumab and lower in ipilimumab > nivolumab responding patients are shown in the bottom left quadrants. The number of immunophenotypes significantly decreased after nivolumab and higher in ipilimumab > nivolumab responding patients are shown in the bottom right quadrants. (B) A similar Venn diagram, along with quadrant plots, is shown for significant ipilimumab changes and nivolumab-ipilimumab response/survival–associated immunophenotypes. (C and D) Delta values (weeks 13–0) for the 210 immunophenotypes significantly changed after nivolumab or after ipilimumab and associated with response/survival in ipilimumab > nivolumab– or nivolumab > ipilimumab–treated patients were used in an elastic net regularized regression model to categorize patient response. (C) The ROC and AUC for patients in the nivolumab > ipilimumab–treated cohort are shown. The model values for nonresponding and responding patients are plotted in the bottom right inlay. Box plots show median ± quartiles, with whiskers indicating range. (D) Results for ipilimumab > nivolumab–treated patients are likewise shown.