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

• Published in: Cancer Immunology, Immunotherapy Immunotherapy, 2014-08, Vol.63 (8), p.779-786
• Main Authors: Hu, Yinin, Petroni, Gina R., Olson, Walter C., Czarkowski, Andrea, Smolkin, Mark E., Grosh, William W., Chianese-Bullock, Kimberly A., Slingluff, Craig L.
• Format: Article
• Language: English
• Subjects: Alleles; Amino Acid Sequence; Amino acids; Antigens; Cancer; Cancer Research; Cancer Vaccines - administration & dosage; Cancer Vaccines - immunology; CD4 Antigens - biosynthesis; CD4 Antigens - immunology; Cell Differentiation; Cytotoxicity; Epitopes - immunology; FDA approval; HLA Antigens - genetics; HLA Antigens - immunology; Humans; Immunization; Immunology; Immunotherapy; Lymphocytes; Medicine; Medicine & Public Health; Melanoma; Melanoma - immunology; Melanoma, Cutaneous Malignant; Molecular Sequence Data; Oncology; Original Article; Patients; Peptides; Peptides - immunology; Skin Neoplasms; Vaccines
• ISSN: 0340-7004; 1432-0851
• DOI: 10.1007/s00262-014-1551-x

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-A3 281–295 (49 %) and tyrosinase 386–406 (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.