title: Immunogenicity, including vitiligo, and feasibility of vaccination with autologous GM-CSF-transduced tumor cells in metastatic melanoma patients.
abstract: OBJECTIVE
  To determine the feasibility, toxicity, and immunologic effects of vaccination with autologous tumor cells retrovirally transduced with the GM-CSF gene, we performed a phase I/II vaccination study in stage IV metastatic melanoma patients.
  
  
  METHODS
  Sixty-four patients were randomly assigned to receive three vaccinations of high-dose or low-dose tumor cells at 3-week intervals. Tumor cell vaccine preparation succeeded for 56 patients (88%), but because of progressive disease, the well-tolerated vaccination was completed in only 28 patients. We analyzed the priming of T cells against melanoma antigens, MART-1, tyrosinase, gp100, MAGE-A1, and MAGE-A3 using human leukocyte antigen/peptide tetramers and functional assays.
  
  
  RESULTS
  The high-dose vaccination induced the infiltration of T cells into the tumor tissue. Three of 14 patients receiving the high-dose vaccine showed an increase in MART-1- or gp100-specific T cells in the peripheral blood during vaccination. Six patients experienced disease-free survival for more than 5 years, and two of these patients developed vitiligo at multiple sites after vaccination. MART-1- and gp100-specific T cells were found infiltrating in vitiligo skin. Upon vaccination, the T cells acquired an effector phenotype and produced interferon-gamma on specific antigenic stimulation.
  
  
  CONCLUSIONS
  We conclude that vaccination with GM-CSF-transduced autologous tumor cells has limited toxicity and can enhance T-cell activation against melanocyte differentiation antigens, which can lead to vitiligo. Whether the induction of autoimmune vitiligo may prolong disease-free survival of metastatic melanoma patients who are surgically rendered as having no evidence of disease before vaccination is worthy of further investigation.
authors.affiliation: Clinical Immunotherapy, Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Rosalie M
authors.initials: RM
authors.lastname: Luiten
authors.forename: Esther W M
authors.initials: EW
authors.lastname: Kueter
authors.forename: Wolter
authors.initials: W
authors.lastname: Mooi
authors.forename: Maarten P W
authors.initials: MP
authors.lastname: Gallee
authors.forename: Elaine M
authors.initials: EM
authors.lastname: Rankin
authors.forename: Winald R
authors.initials: WR
authors.lastname: Gerritsen
authors.forename: Shirley M
authors.initials: SM
authors.lastname: Clift
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Nooijen
authors.forename: Pauline
authors.initials: P
authors.lastname: Weder
authors.forename: Willeke F
authors.initials: WF
authors.lastname: van de Kasteele
authors.forename: Johan
authors.initials: J
authors.lastname: Sein
authors.forename: Paul C M
authors.initials: PC
authors.lastname: van den Berk
authors.forename: Omgo E
authors.initials: OE
authors.lastname: Nieweg
authors.forename: Anton M
authors.initials: AM
authors.lastname: Berns
authors.forename: Hergen
authors.initials: H
authors.lastname: Spits
authors.forename: Gijsbert C
authors.initials: GC
authors.lastname: de Gast
mesh_terms: D000276:Adjuvants, Immunologic; D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D003602:Cytotoxicity, Immunologic; D004334:Drug Administration Schedule; D005240:Feasibility Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology; D014820:Vitiligo / Q000209:etiology
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019496:Cancer Vaccines; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D016178:Granulocyte-Macrophage Colony-Stimulating Factor