title: Increases in Absolute Lymphocytes and Circulating CD4+ and CD8+ T Cells Are Associated with Positive Clinical Outcome of Melanoma Patients Treated with Ipilimumab.
abstract: OBJECTIVE
  To investigate changes of peripheral blood biomarkers and their impact on clinical outcome following treatment with ipilimumab in advanced melanoma patients.
  
  
  METHODS
  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.
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany. Department of Internal Medicine II, University Medical Center, Tübingen, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Martens
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany. Department of Internal Medicine II, University Medical Center, Tübingen, Germany.
authors.forename: Kilian
authors.initials: K
authors.lastname: Wistuba-Hamprecht
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Jianda
authors.initials: J
authors.lastname: Yuan
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Postow
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York.
authors.forename: Phillip
authors.initials: P
authors.lastname: Wong
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Mariaelena
authors.initials: M
authors.lastname: Capone
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Madonna
authors.affiliation: Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France.
authors.forename: Amir
authors.initials: A
authors.lastname: Khammari
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Bastian
authors.initials: B
authors.lastname: Schilling
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Sucker
authors.affiliation: Department of Dermatology, University Hospital, West German Cancer Center, University Duisburg-Essen, Essen, Germany. German Cancer Consortium (DKTK), Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schadendorf
authors.affiliation: Departments of Clinical Epidemiology and Applied Biostatistics, University of Tübingen, Tübingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Martus
authors.affiliation: Department of Oncodermatology, INSERM Research Unit 892, University Hospital, Nantes, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Dreno
authors.affiliation: Istituto Nazionale Tumori Fondazione Pascale, Naples, Italy.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Ascierto
authors.affiliation: Memorial Sloan Kettering Cancer Center, New York, New York. Weill Cornell Medical College, New York, New York.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
authors.affiliation: Department of Internal Medicine II, University Medical Center, Tübingen, Germany. School of Science and Technology, College of Arts and Science, Nottingham Trent University, Nottingham, United Kingdom.
authors.forename: Graham
authors.initials: G
authors.lastname: Pawelec
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Garbe
authors.affiliation: Department of Dermatology, University Medical Center, Tübingen, Germany. benjamin.weide@med.uni-tuebingen.de.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Weide
mesh_terms: D000328:Adult; D000368:Aged; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D006801:Humans; D000074324:Ipilimumab / Q000627:therapeutic use*; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality; D008875:Middle Aged; D016016:Proportional Hazards Models; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000401:mortality
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; D000074324:Ipilimumab