Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are Associated with Positive Clinical Outcome of Melanoma Patients Treated with Ipilimumab

Alexander A Martens (1, 2) , Kilian Wistuba-Hamprecht (1, 2) , Jianda Yuan (3) , Michael A Postow (4, 3) , Phillip Wong (3) , Mariaelena Capone (5) , Gabriele Madonna (5) , Amir A Khammari (6, 7) , Bastian Schilling (8, 9) , Antje A Sucker (8, 9) , Dirk D Schadendorf (9, 8) , Peter Martus (10) , Brigitte D Dreno (6, 7) , Paolo A Ascierto (5) , Jedd D Wolchok (3, 4) , Graham Pawelec (1, 11) , Claus Garbe (2) , Benjamin Weide (2)

1 Department of Internal Medicine II
2 Department of Dermatology [Tubingen, Germany]
3 Memorial Sloane Kettering Cancer Center [New York]
4 Weill Medical College of Cornell University [New York]
5 Istituto Nazionale Tumori IRCCS
6 Service de dermatologie [Nantes]
7 CRCNA - Centre de Recherche en Cancérologie Nantes-Angers
8 German Cancer Consortium
9 Department of Dermatology
10 University of Tübingen
11 School of Science and Technology [Nottingham, U.K.]

Purpose: To investigate changes of peripheral blood biomar-kers 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. End-points 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 ¼ 0.003) and in percentages of CD4 þ and CD8 þ T cells 8 to 14 weeks (P ¼ 0.001 and P ¼ 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 myeloid-derived 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 þ and CD8 þ T cells reflect changes associated with positive outcome. These changes represent surrogate marker candidates and warrant further validation.

Domaines: Cancer

Alexander A Martens, Kilian Wistuba-Hamprecht, Jianda Yuan, Michael A Postow, Phillip Wong, et al.. 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, 2016, 22 (19), pp.4848-4858. ⟨10.1158/1078-0432.CCR-16-0249⟩. ⟨inserm-01408937⟩