Immunologic hierarchy, class II MHC promiscuity, and epitope spreading of a melanoma helper peptide vaccine

Cancer Immunol Immunother. 2014 Aug;63(8):779-86. doi: 10.1007/s00262-014-1551-x. Epub 2014 Apr 23.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Alleles
  • Amino Acid Sequence
  • CD4 Antigens / biosynthesis
  • CD4 Antigens / immunology
  • Cancer Vaccines / administration & dosage*
  • Cancer Vaccines / immunology*
  • Cell Differentiation
  • Epitopes / immunology*
  • HLA Antigens / genetics*
  • HLA Antigens / immunology*
  • Humans
  • Melanoma / immunology*
  • Molecular Sequence Data
  • Peptides / immunology*
  • Skin Neoplasms

Substances

  • CD4 Antigens
  • Cancer Vaccines
  • Epitopes
  • HLA Antigens
  • Peptides

Supplementary concepts

  • Melanoma, Cutaneous Malignant