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 1

Overview of Approach.

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Overview of Approach. (A) PMBC samples were obtained from metastatic mel...
(A) PMBC samples were obtained from metastatic melanoma patients treated as part of the Checkmate-064 clinical trial. Patients were treated with sequential NIVO > IPI (Cohort A) or IPI > NIVO (Cohort B). Samples were collected before treatment (baseline) and after first agent (week 13). The indicated number of samples for each cohort and time point, broken down by patient response (responders in blue; nonresponders in red) are given. (B) A generalized illustration of how the data were assessed using combinatorics and CytoBrute is shown. Briefly, for each cell population (CD3+CD8+ in the example illustration), cells were assessed for single markers and all combinations up to 15 markers in complexity. This was performed for 4 separate flow cytometry panels. (C) The number of theoretical immunophenotypes for 1–15 markers in complexity is shown by blue bars and the corresponding number of actual immunophenotypes measured in the data set are shown in red. (D) For the actual immunophenotypes measured, the number of positive markers measured at each increment of complexity is shown.