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 3

Immunophenotypes associated with patient response are distinct in nivolumab and ipilimumab sequentially treated patients.

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Immunophenotypes associated with patient response are distinct in nivolu...
(A) The median frequency of immunophenotypes that are significantly different for both response (determined by Mann-Whitney U test) and overall survival (determined by Mantel-Cox test) in nonresponding patients are shown on the x axis and in responding patients on the y axis for nivolumab > ipilimumab–treated patient samples. Each dot represents an immunophenotype and is colored by the P value of the comparison between responders and nonresponders, for that cell population. The purple dotted line with a slope of 1 corresponds to no change in median frequency. Significantly different immunophenotypes in baseline patient samples are shown in the left panel, and significantly different immunophenotypes in week-13 patient samples are shown in the right panel. (B) Immunophenotypes for ipilimumab > nivolumab–treated patients are likewise shown. (C) A Venn diagram is shown with the number of immunophenotypes significantly different in each cohort and time point. (D) A graph of 1 of the 2 related significantly different immunophenotypes overlapping between nivolumab > ipilimumab– and ipilimumab > nivolumab–treated patients at baseline is shown. Frequencies of the populations shown are plotted by cohort and response. Each dot represents an individual patient sample. Box plots show median ± quartiles, with whiskers indicating range. (E) A survival plot for this immunophenotype is also shown. Patients were stratified based on median frequency of the immunophenotype. Nivolumab > ipilimumab–treated patients with greater than median frequencies are shown in blue and less than median frequency in green. Ipilimumab > nivolumab–treated patients with greater than median frequencies are shown in red and less than median are shown in purple.