Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab

Alexander Martens, Kilian Wistuba-Hamprecht, Jianda Yuan, Michael A. Postow, Phillip Wong, Mariaelena Capone, Gabriele Madonna, Amir Khammari, Bastian Schilling, Antje Sucker, Dirk Schadendorf, Peter Martus, Brigitte Dreno, Paolo A. Ascierto, Jedd D. Wolchok, Graham Pawelec, Claus Garbe, Benjamin Weide

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Abstract

Purpose: To investigate changes of peripheral blood biomarkers and their impact on clinical outcome following treatment with ipilimumab in advanced melanoma patients. Experimental Design: Changes in blood counts and the frequency of circulating immune cell populations analyzed by flow cytometry were investigated in 82 patients to compare baseline values with different time-points after starting ipilimumab. Endpoints were overall survival (OS) and best clinical response. Statistical calculations were done by Wilcoxon-matched pairs tests, Fisher exact test, Kaplan-Meier analysis, and Cox regression analysis. Results: Increases in absolute lymphocyte counts (ALC) 2 to 8 weeks (P=0.003) and in percentages of CD4+ and CD8+ T cells 8 to 14 weeks (P = 0.001 and P = 0.02) after the first dose of ipilimumab were correlated with improved survival. These associations did not meet significance criteria, when conservatively adjusted for multiple testing, but were additionally correlated with clinical responses (all P < 0.05). However, validation is required. Increases in all three factors were observed in 36% of patients, who had a favorable outcome and survival probabilities of 93.3% and 63.8% at 12 and 24 months, respectively. A partial or complete response was observed in 71% of these patients compared with only 8% in patients with decreases in ≥1 of the 3 factors, respectively. Changes of regulatory T cells or myeloidderived suppressor cells were not associated with OS. Conclusions: Increases of ALC observed 2 to 8 weeks after initiation of ipilimumab and delayed increases in CD4+ and CD8+ T cells reflect changes associated with positive outcome. These changes represent surrogate marker candidates and warrant further validation. Clin Cancer Res; 22(19); 4848-58.

Original languageEnglish
Pages (from-to)4848-4858
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number19
DOIs
Publication statusPublished - Oct 1 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Martens, A., Wistuba-Hamprecht, K., Yuan, J., Postow, M. A., Wong, P., Capone, M., Madonna, G., Khammari, A., Schilling, B., Sucker, A., Schadendorf, D., Martus, P., Dreno, B., Ascierto, P. A., Wolchok, J. D., Pawelec, G., Garbe, C., & Weide, B. (2016). Increases in absolute lymphocytes and circulating CD4+ and CD8+ T cells are associated with positive clinical outcome of melanoma patients treated with ipilimumab. Clinical Cancer Research, 22(19), 4848-4858. https://doi.org/10.1158/1078-0432.CCR-16-0249