title: Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine.
abstract: Immunization with a combination melanoma helper peptide (6MHP) vaccine has been shown to induce CD4(+) T cell responses, which are associated with patient survival. In the present study, we define the relative immunogenicity and HLA allele promiscuity of individual helper peptides and identify helper peptide-mediated augmentation of specific CD8(+) T cell responses. Thirty-seven participants with stage IIIB-IV melanoma were vaccinated with 6MHP in incomplete Freund's adjuvant. The 6MHP vaccine is comprised of 6 peptides representing melanocytic differentiation proteins gp100, tyrosinase, Melan-A/MART-1, and cancer testis antigens from the MAGE family. CD4(+) and CD8(+) T cell responses were assessed in peripheral blood and in sentinel immunized nodes (SIN) by thymidine uptake after exposure to helper peptides and by direct interferon-γ ELIspot assay against 14 MHC class I-restricted peptides. Vaccine-induced CD4(+) T cell responses to individual epitopes were detected in the SIN of 63 % (22/35) and in the peripheral blood of 38 % (14/37) of participants for an overall response rate of 65 % (24/37). The most frequently immunogenic peptides were MAGE-A3281-295 (49 %) and tyrosinase386-406 (32 %). Responses were not limited to HLA restrictions originally described. Vaccine-associated CD8(+) T cell responses against class I-restricted peptides were observed in 45 % (5/11) of evaluable participants. The 6MHP vaccine induces both CD4(+) and CD8(+) T cell responses against melanoma antigens. CD4(+) T cell responses were detected beyond reported HLA-DR restrictions. Induction of CD8(+) T cell responses suggests epitope spreading and systemic activity mediated at the tumor site.
authors.affiliation: Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, PO Box 800679, Charlottesville, VA, 22908-0679, USA, yh9b@virginia.edu.
authors.forename: Yinin
authors.initials: Y
authors.lastname: Hu
authors.forename: Gina R
authors.initials: GR
authors.lastname: Petroni
authors.forename: Walter C
authors.initials: WC
authors.lastname: Olson
authors.forename: Andrea
authors.initials: A
authors.lastname: Czarkowski
authors.forename: Mark E
authors.initials: ME
authors.lastname: Smolkin
authors.forename: William W
authors.initials: WW
authors.lastname: Grosh
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Chianese-Bullock
authors.forename: Craig L
authors.initials: CL
authors.lastname: Slingluff
mesh_terms: D000483:Alleles; D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000096:biosynthesis / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D002454:Cell Differentiation; D000939:Epitopes / Q000276:immunology*; D006680:HLA Antigens / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D008545:Melanoma / Q000276:immunology*; D008969:Molecular Sequence Data; D010455:Peptides / Q000276:immunology*; D012878:Skin Neoplasms; D000096142:Cutaneous Malignant Melanoma
chemical_list: D015704:CD4 Antigens; D019496:Cancer Vaccines; D000939:Epitopes; D006680:HLA Antigens; D010455:Peptides
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