title: Effect of granulocyte/macrophage colony-stimulating factor on circulating CD8+ and CD4+ T-cell responses to a multipeptide melanoma vaccine: outcome of a multicenter randomized trial.
abstract: OBJECTIVE
  Granulocyte/macrophage colony-stimulating factor (GM-CSF) administered locally together with vaccines can augment T-cell responses in animal models. Human experience has been limited to small and uncontrolled trials. Thus, a multicenter randomized phase II trial was done to determine whether local administration of GM-CSF augments immunogenicity of a multipeptide vaccine. It also assessed immunogenicity of administration in one versus two vaccine sites.
  
  
  METHODS
  One hundred twenty-one eligible patients with resected stage IIB to IV melanoma were vaccinated with 12 MHC class I-restricted melanoma peptides to stimulate CD8+ T cells plus a HLA-DR-restricted tetanus helper peptide to stimulate CD4+ T cells, emulsified in incomplete Freund's adjuvant, with or without 110 microg GM-CSF. Among 119 evaluable patients, T-cell responses were assessed by IFN-gamma ELIspot assay and tetramer analysis. Clinical outcomes were recorded.
  
  
  RESULTS
  CD8+ T-cell response rates to the 12 MHC class I-restricted melanoma peptides (by day 50) with or without GM-CSF were 34% and 73%, respectively (P < 0.001), by direct ELIspot assay. Tetramer analyses corroborated the functional data. CD4+ T-cell responses to tetanus helper peptide were higher without GM-CSF (95% versus 77%; P = 0.005). There was no significant difference by number of vaccine sites. Three-year overall and disease-free survival estimates (95% confidence interval) were 76% (67-83%) and 52% (43-61%), respectively, with too few events to assess differences by study group.
  
  
  CONCLUSIONS
  High immune response rates for this multipeptide vaccine were achieved, but CD8+ and CD4+ T-cell responses were lower when administered with GM-CSF. These data challenge the value of local GM-CSF as a vaccine adjuvant in humans.
authors.affiliation: Department of Surgery/Division of Surgical Oncology, Department of Public Health Sciences, and Department of Medicine/Division of Hematology-Oncology, University of Virginia, Charlottesville, Virginia, USA.
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
authors.forename: Gina R
authors.initials: GR
authors.lastname: Petroni
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smolkin
authors.forename: Merrick I
authors.initials: MI
authors.lastname: Ross
authors.forename: Naomi B
authors.initials: NB
authors.lastname: Haas
authors.forename: William W
authors.initials: WW
authors.lastname: Grosh
authors.forename: Marc E
authors.initials: ME
authors.lastname: Boisvert
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chianese-Bullock
mesh_terms: D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000378:metabolism / Q000627:therapeutic use*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D007371:Interferon-gamma / Q000378:metabolism; D008285:Major Histocompatibility Complex; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000628:therapy; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry; D016896:Treatment Outcome; D022223:Vaccines, Subunit / Q000627:therapeutic use*
chemical_list: D019496:Cancer Vaccines; D010455:Peptides; D022223:Vaccines, Subunit; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor