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. 2016 Oct 1;22(19):4848-4858.
doi: 10.1158/1078-0432.CCR-16-0249. Epub 2016 May 11.

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

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 et al. Clin Cancer Res. .

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 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+ 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. ©2016 AACR.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

J. Yuan is an employee of Merck. M.A. Postow reports receiving honoraria from Bristol-Myers Squibb and Merck, and is a consultant/advisory board member for and reports receiving commercial research grants from Bristol-Myers Squibb. P. Wong is a consultant/advisory board member for Merck. B. Schilling reports receiving speakers bureau honoraria from, is a consultant/advisory board member for, and reports receiving commercial research grants from Bristol-Myers Squibb. P.A. Ascierto is a consultant/advisory board member for Amgen, Array, Bristol-Myers Squibb, MSD, Novartis, Roche-Genentech, and Ventana, and reports receiving commercial research grants from Bristol-Myers Squibb, Roche-Genentech, and Ventana. J.D. Wolchok is a consultant/advisory board member for and reports receiving commercial research grants from Bristol-Myers Squibb and Medimmune. G. Pawelec reports receiving speakers bureau honoraria from Astellas, Cellgene, Clasado, and Pfizer. C. Garbe is a consultant/advisory board member for Amgen, Bristol-Myers Squibb, Leo Pharma, Merck/MSD, Novartis, Roche, and reports receiving commercial research grants from Bristol-Myers Squibb, Novartis, and Roche, and speakers bureau honoraria and travel reimbursement from Amgen, Bristol-Myers Squibb, Leo Pharma, Merck/MSD, Novartis, and Roche. B. Weide reports receiving commercial research grants, honoraria, and travel support from Bristol-Myers Squibb. No potential conflicts of interest were disclosed by the other authors.

Figures

Figure 1
Figure 1
OS according to changes in ALC, leucocyte counts, eosinophil counts, and CD4+ and CD8+ frequencies during ipilimumab therapy. Kaplan–Meier analysis of OS according to early changes (increase vs. decrease) of absolute leucocyte counts (A), ALC (B), and delayed changes in AECs (C) and changes in percentage of CD4+ (D) and CD8+ (E) T cells observed during ipilimumab treatment. Censoring is indicated by vertical lines; P values were calculated by log-rank statistics.
Figure 2
Figure 2
OS and best tumor response based on combined changes in ALC and frequencies of CD4+ T cells. Kaplan–Meier analysis of OS for patients based on combined early changes in ALCs and delayed changes of frequencies of CD4+ T cells. Patients were grouped based on whether both factors showed an increase versus patients where one or no factor increased (A). Best overall tumor response was investigated as either clinical benefit (complete response, partial response, or stable disease) or response (complete response or partial response) defined via irRC. The best overall tumor response was not available for 5 of 44 patients with complete biomarker data (changes in ALC, CD4+ T cells, and CD8+ T cells; B).
Figure 3
Figure 3
OS and best tumor response based on combined changes in ALC and frequencies of CD4+ and CD8+ T cells. Kaplan–Meier analysis of OS for patients based on combined early changes in ALCs and delayed changes of frequencies of CD4+ and CD8+ T cells. Changes were defined merely as increase versus decrease. Patients were grouped based on whether all three factors showed an increase versus patients with an increase in 0–2 factors (A). Best overall tumor response was investigated as either clinical benefit (complete response, partial response, or stable disease) or response (complete response or partial response) defined via irRC. The best overall tumor response was not available for 5 of 44 patients with complete biomarker data (changes in ALC, CD4+ T cells, and CD8+ T cells; B).
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