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Title: Regulatory T-cell-mediated attenuation of T-cell responses to the NY-ESO-1 ISCOMATRIX vaccine in patients with advanced malignant melanoma.
Austin Authors: Nicholaou, Theo;Ebert, Lisa M;Davis, Ian D;McArthur, Grant A;Jackson, Heather M;Dimopoulos, Nektaria;Tan, Bee;Maraskovsky, Eugene;Miloradovic, Lena;Hopkins, Wendie;Pan, Linda;Venhaus, Ralph;Hoffman, Eric W;Chen, Weisan;Cebon, Jonathan S 
Affiliation: Ludwig Institute for Cancer Research, Austin Health, Peter MacCallum Cancer Centre, CSL Limited, Melbourne, Victoria, Australia
Issue Date: 10-Mar-2009
Publication information: Clinical Cancer Research 2009; 15(6): 2166-73
Abstract: 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.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.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.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.
Gov't Doc #: 19276262
DOI: 10.1158/1078-0432.CCR-08-2484
Journal: Clinical Cancer Research
Type: Journal Article
Subjects: Adjuvants, Immunologic.administration & dosage
Aged, 80 and over
Antigens, Neoplasm.administration & dosage.immunology
Cancer Vaccines.administration & dosage.immunology
Cholesterol.administration & dosage
Drug Combinations
Hypersensitivity, Delayed.etiology
Membrane Proteins.administration & dosage.immunology
Middle Aged
Phospholipids.administration & dosage
Saponins.administration & dosage
T-Lymphocytes, Regulatory.physiology
Appears in Collections:Journal articles

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