Biomarkers on melanoma patient T Cells associated with ipilimumab treatment

BACKGROUND:Ipilimumab induces long-lasting clinical responses in a minority of patients with metastatic melanoma. To better understand the mechanism(s) of action and to identify novel biomarkers associated with the clinical benefit and toxicity of ipilimumab, baseline characteristics and changes in CD4+ and CD8+ T cells from melanoma patients receiving ipilimumab were characterized by gene profiling and flow cytometry.METHODS:Microarray analysis of flow-cytometry purified CD4+ and CD8+ T cells was employed to assess gene profiling changes induced by ipilimumab. Selected molecules were further investigated by flow cytometry on pre, 3-month and 6-month post-treatment specimens.RESULTS:Ipilimumab up-regulated Ki67 and ICOS on CD4+ and CD8+ cells at both 3- and 6-month post ipilimumab (p less than or equal to 0.001), decreased CCR7 and CD25 on CD8+ at 3-month post ipilimumab (p less than or equal to 0.02), and increased Gata3 on CD4+ and CD8+ cells at 6-month post ipilimumab (p less than or equal to 0.004). Increased EOMES+CD8+, GranzymeB+EOMES+CD8+ and decreased Ki67+EOMES+CD4+ T cells at 6 months were significantly associated with relapse (all p less than or equal to 0.04). Decreased Ki67+CD8+ T cells were significantly associated with the development of irAE (p=0.02). At baseline, low Ki67+EOMES+CD8+ T cells were associated with relapse (p less than or equal to 0.001), and low Ki67+EOMES+CD4+ T cells were associated with irAE (p less than or equal to 0.008).CONCLUSIONS:Up-regulation of proliferation and activation signals in CD4+ and CD8+ T cells were pharmacodynamic markers for ipilimumab. Ki67+EOMES+CD8+ and Ki67+EOMES+CD4+ T cells at baseline merit further testing as biomarkers associated with outcome and irAEs, respectively.

Journal of Translational Medicine , article en libre accès, 2011

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