title: Pilot study of granulocyte-macrophage colony-stimulating factor and interleukin-2 as immune adjuvants for a melanoma peptide vaccine.
abstract: Thus far, peptide vaccines used to stimulate tumor-specific immune responses in patients with melanoma have been largely unsuccessful. Granulocyte-macrophage colony-stimulating factor and interleukin-2 are immune-potentiating cytokines that have improved vaccine responses in preclinical models. We hypothesized that higher doses of granulocyte-macrophage colony-stimulating factor and addition of low-dose interleukin-2 might augment responses to vaccine antigens. Patients with resected stage II, III, or IV melanoma were treated with vaccines containing three melanoma-associated peptides [MART-1a, gp100(207-217), and survivin], along with 300 or 500 mcg granulocyte-macrophage colony-stimulating factor in Montanide ISA. Cohorts of patients received low-dose subcutaneous interleukin-2 on days 7-20 after vaccination. Induction of a response was defined as either doubling of cytotoxic T lymphocyte frequency from baseline or increase in frequency from undetectable (<0.05%) to detectable. Leukocyte subsets and plasma cytokines were analyzed before and after vaccination. Cytotoxic T lymphocyte responses to MART-1a, gp100(207-217), and survivin were induced in 11, 16, and 14 of 19 patients, respectively. Responses were not higher in patients receiving 500 mcg granulocyte-macrophage colony-stimulating factor or low-dose interleukin-2 than in patients receiving 300 mcg granulocyte-macrophage colony-stimulating factor only. Interleukin-2 treatment (in nine patients) led to increases in natural killer cells and T regulatory cells compared with no interleukin-2 treatment (nine patients). Multiple plasma cytokines were transiently induced during vaccination. Neither increasing the dose of granulocyte-macrophage colony-stimulating factor nor addition of low-dose interleukin-2 resulted in an increase in the frequency of vaccine-specific cytotoxic T lymphocytes to a melanoma peptide vaccine. The increase in T regulatory cells associated with interleukin-2 treatment suggests that interleukin-2 may be immunosuppressive in this setting.
authors.affiliation: Department of Oncology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Block
authors.forename: Vera J
authors.initials: VJ
authors.lastname: Suman
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Nevala
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Kottschade
authors.forename: Edward T
authors.initials: ET
authors.lastname: Creagan
authors.forename: Judith S
authors.initials: JS
authors.lastname: Kaur
authors.forename: Jorge Fernando
authors.initials: JF
authors.lastname: Quevedo
authors.forename: Robert R
authors.initials: RR
authors.lastname: McWilliams
authors.forename: Svetomir N
authors.initials: SN
authors.lastname: Markovic
mesh_terms: D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology / Q000627:therapeutic use*; D058965:MART-1 Antigen / Q000276:immunology; D008297:Male; D008545:Melanoma / Q000276:immunology / Q000601:surgery / Q000628:therapy*; D008875:Middle Aged; D010865:Pilot Projects; D000077022:Survivin; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use*; D055815:Young Adult; D058951:gp100 Melanoma Antigen / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; C107489:BIRC5 protein, human; D019496:Cancer Vaccines; D051034:Inhibitor of Apoptosis Proteins; D007376:Interleukin-2; D058965:MART-1 Antigen; C548667:MLANA protein, human; C548637:PMEL protein, human; D000077022:Survivin; D022223:Vaccines, Subunit; D058951:gp100 Melanoma Antigen; D016178:Granulocyte-Macrophage Colony-Stimulating Factor