title: Induction of cytotoxic T cells as a novel independent survival factor in malignant melanoma with percutaneous peptide immunization.
abstract: BACKGROUND
  Malignant melanoma (MM) often shows multiple chemo-resistance, leading to poor prognosis of the patients. Therapeutic anti-cancer vaccination may be a feasible way to prolong the survival of patients. We have demonstrated that application of antigenic peptides via the tape-stripped, horny layer-removed skin, known as percutaneous peptide immunization (PPI), induces tumor cell-specific cytotoxic T lymphocytes (CTLs) in rodents and humans.
  
  
  OBJECTIVE
  To evaluate clinical significance of PPI in advanced MM patients.
  
  
  METHODS
  We performed PPI in 59 patients undergoing advanced MM with Melan-A, tyrosinase, MAGE-2, MAGE-3 and gp-100 peptides based on HLA typing in individuals. The induction of CTLs was assessed by the tetramer or pentamer flow cytometry in 35 patients. Patients showing positive CTL responses to all antigens were defined as complete responder (n=18), and those showing negative responses to at least one applied antigen were classified as incomplete responder (n=17). The primary endpoint of the study was overall survival (OS). For statistical analysis, log-rank test, univariate and multivariate Cox proportional hazard model were used.
  
  
  RESULTS
  OS of the complete responders was longer than that of the incomplete responders (median survival time: 55.8 vs 20.3 months, log rank P=0.089). A hazard ratio for the complete responders relative to the incomplete responders was 0.23 (95% confidence interval: 0.06-0.93, P=0.039) in a multivariate Cox proportional hazard model.
  
  
  CONCLUSIONS
  The induction of CTLs was a novel independent survival factor, and the induction of peptide-specific CTLs by PPI contributes to the prolonged survival and represents an impact on therapeutic approaches in MM. Unique trial number: UMIN000005706.
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan. Electronic address: fujiyama@hama-med.ac.jp.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Fujiyama
authors.affiliation: Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Oze
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Hashizume
authors.affiliation: Department of Preventive Medicine, Kyusyu University, Japan.
authors.forename: Keitaro
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Dermatology, University of Occupational and Environmental Health, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Hino
authors.affiliation: Department of Dermatology, Osaka City University Graduate School of Medicine, Japan.
authors.forename: Riei
authors.initials: R
authors.lastname: Kamo
authors.affiliation: Imayama Shuhei Clinic & Lab, Japan.
authors.forename: Shuhei
authors.initials: S
authors.lastname: Imayama
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hirakawa
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan.
authors.forename: Taisuke
authors.initials: T
authors.lastname: Ito
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Takigawa
authors.affiliation: Department of Dermatology, Hamamatsu University School of Medicine, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Tokura
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology; D005260:Female; D006680:HLA Antigens / Q000276:immunology; D006801:Humans; D007114:Immunization; D058965:MART-1 Antigen / Q000008:administration & dosage; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D058950:Melanoma-Specific Antigens / Q000008:administration & dosage; D008875:Middle Aged; D014442:Monophenol Monooxygenase / Q000008:administration & dosage; D015999:Multivariate Analysis; D010446:Peptide Fragments / Q000008:administration & dosage* / Q000276:immunology; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality / Q000473:pathology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D058951:gp100 Melanoma Antigen / Q000008:administration & dosage
chemical_list: D019496:Cancer Vaccines; D006680:HLA Antigens; D058965:MART-1 Antigen; C548667:MLANA protein, human; D058950:Melanoma-Specific Antigens; D010446:Peptide Fragments; D058951:gp100 Melanoma Antigen; D014442:Monophenol Monooxygenase
keywords: Cytotoxic T lymphocytes; Melanoma; Percutaneous peptide immunization