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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.
AuthorsYinin Hu, Gina R Petroni, Walter C Olson, Andrea Czarkowski, Mark E Smolkin, William W Grosh, Kimberly A Chianese-Bullock, Craig L Slingluff Jr
JournalCancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 63 Issue 8 Pg. 779-86 (Aug 2014) ISSN: 1432-0851 [Electronic] Germany
PMID24756419 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • CD4 Antigens
  • Cancer Vaccines
  • Epitopes
  • HLA Antigens
  • Peptides
Topics
  • Alleles
  • Amino Acid Sequence
  • CD4 Antigens (biosynthesis, immunology)
  • Cancer Vaccines (administration & dosage, immunology)
  • Cell Differentiation
  • Epitopes (immunology)
  • HLA Antigens (genetics, immunology)
  • Humans
  • Melanoma (immunology)
  • Molecular Sequence Data
  • Peptides (immunology)
  • Skin Neoplasms

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