title: Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma.
abstract: OBJECTIVE
  NY-ESO-1 is a highly immunogenic antigen expressed in a variety of malignancies, making it an excellent target for cancer vaccination. We recently developed a vaccine consisting of full-length recombinant NY-ESO-1 protein formulated with ISCOMATRIX adjuvant, which generated strong humoral and T-cell-mediated immune responses and seemed to reduce the risk of disease relapse in patients with fully resected melanoma. This study examines the clinical and immunologic efficacy of the same vaccine in patients with advanced metastatic melanoma.
  
  
  METHODS
  Delayed-type hypersensitivity responses, circulating NY-ESO-1-specific CD4(+) and CD8(+) T cells, and proportions of regulatory T cells (Treg) were assessed in patients.
  
  
  RESULTS
  In contrast to patients with minimal residual disease, advanced melanoma patients showed no clinical responses to vaccination. Although strong antibody responses were mounted, the generation of delayed-type hypersensitivity responses was significantly impaired. The proportion of patients with circulating NY-ESO-1-specific CD4(+) T cells was also reduced, and although many patients had CD8(+) T cells specific to a broad range of NY-ESO-1 epitopes, the majority of these responses were preexisting. Tregs were enumerated in the blood by flow cytometric detection of cells with a CD4(+)CD25(+)FoxP3(+) and CD4(+)CD25(+)CD127(-) phenotype. Patients with advanced melanoma had a significantly higher proportion of circulating Treg compared with those with minimal residual disease.
  
  
  CONCLUSIONS
  Our results point to a tumor-induced systemic immune suppression, showing a clear association between the stage of melanoma progression, the number of Treg in the blood, and the clinical and immunologic efficacy of the NY-ESO-1 ISCOMATRIX cancer vaccine.
authors.affiliation: Ludwig Institute for Cancer Research, Austin Health, Peter MacCallum Cancer Centre, CSL Limited, Melbourne, Victoria, Australia.
authors.forename: Theo
authors.initials: T
authors.lastname: Nicholaou
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ebert
authors.forename: Ian D
authors.initials: ID
authors.lastname: Davis
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
authors.forename: Heather
authors.initials: H
authors.lastname: Jackson
authors.forename: Nektaria
authors.initials: N
authors.lastname: Dimopoulos
authors.forename: Bee
authors.initials: B
authors.lastname: Tan
authors.forename: Eugene
authors.initials: E
authors.lastname: Maraskovsky
authors.forename: Lena
authors.initials: L
authors.lastname: Miloradovic
authors.forename: Wendie
authors.initials: W
authors.lastname: Hopkins
authors.forename: Linda
authors.initials: L
authors.lastname: Pan
authors.forename: Ralph
authors.initials: R
authors.lastname: Venhaus
authors.forename: Eric W
authors.initials: EW
authors.lastname: Hoffman
authors.forename: Weisan
authors.initials: W
authors.lastname: Chen
authors.forename: Jonathan
authors.initials: J
authors.lastname: Cebon
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000951:Antigens, Neoplasm / Q000008:administration & dosage / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D002784:Cholesterol / Q000008:administration & dosage*; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000209:etiology; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008565:Membrane Proteins / Q000008:administration & dosage / Q000276:immunology*; D008875:Middle Aged; D010743:Phospholipids / Q000008:administration & dosage*; D012503:Saponins / Q000008:administration & dosage*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D014611:Vaccination
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D004338:Drug Combinations; C493786:ISCOMATRIX; D008565:Membrane Proteins; D010743:Phospholipids; D012503:Saponins; D002784:Cholesterol