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Cancer Immunology, Immunotherapy

, Volume 63, Issue 8, pp 779–786 | Cite as

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

  • Yinin HuEmail author
  • Gina R. Petroni
  • Walter C. Olson
  • Andrea Czarkowski
  • Mark E. Smolkin
  • William W. Grosh
  • Kimberly A. Chianese-Bullock
  • Craig L. SlingluffJr.
Original Article

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.

Keywords

Melanoma Peptide vaccines CD4 T cells Immunogenicity 

Abbreviations

6MHP

Combination melanoma helper peptide

CTL

Cytotoxic T lymphocyte

PBMC

Peripheral blood mononuclear cell

SI

Stimulation index

SIN

Sentinel immunized node

Notes

Conflicts of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Yinin Hu
    • 1
    Email author
  • Gina R. Petroni
    • 2
  • Walter C. Olson
    • 1
  • Andrea Czarkowski
    • 3
  • Mark E. Smolkin
    • 2
  • William W. Grosh
    • 4
  • Kimberly A. Chianese-Bullock
    • 1
  • Craig L. SlingluffJr.
    • 1
  1. 1.Department of Surgery/Division of Surgical OncologyUniversity of Virginia Health SystemCharlottesvilleUSA
  2. 2.Department of Public Health SciencesUniversity of Virginia Health SystemCharlottesvilleUSA
  3. 3.Cancer CenterUniversity of Virginia Health SystemCharlottesvilleUSA
  4. 4.Department of Medicine/Division of Hematology-OncologyUniversity of Virginia Health SystemCharlottesvilleUSA

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