Multiepitope CD8(+) T cell response to a NY-ESO-1 peptide vaccine results in imprecise tumor targeting

• Published in: The Journal of clinical investigation 2002-12, Vol.110 (12), p.1813-1822
• Main Authors: Dutoit, Valérie, Taub, Robert N, Papadopoulos, Kyriakos P, Talbot, Susan, Keohan, Mary-Louise, Brehm, Michelle, Gnjatic, Sacha, Harris, Paul E, Bisikirska, Brygida, Guillaume, Philippe, Cerottini, Jean-Charles, Hesdorffer, Charles S, Old, Lloyd J, Valmori, Danila
• Format: Article
• Language: English
• Subjects: Antigens, Neoplasm - immunology; Biomedical research; Cancer Vaccines - immunology; Cancer Vaccines - metabolism; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cells, Cultured; Epitopes - immunology; Epitopes - metabolism; HLA-A2 Antigen - immunology; HLA-A2 Antigen - metabolism; Humans; Leiomyosarcoma - immunology; Leiomyosarcoma - therapy; Male; Membrane Proteins; Neoplasms - immunology; Neoplasms - therapy; Protein Binding; Proteins - immunology; Sarcoma, Synovial - immunology; Sarcoma, Synovial - therapy; Vaccines, Subunit - immunology; Vaccines, Subunit - therapeutic use
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI16428

The cancer-testis antigen NY-ESO-1 is one of the most promising candidates for generic vaccination of cancer patients. Here we analyzed the CD8(+) T cell response to a NY-ESO-1 peptide vaccine composed of the two previously defined peptides 157-165 and 157-167, administered with GM-CSF as a systemic adjuvant. The NY-ESO-1 peptide vaccine elicited a CD8(+) T cell response directed against multiple distinct epitopes in the 157-167 region, as revealed by using A2/peptide multimers incorporating overlapping A2 binding peptides in this region. However, only a minor fraction of the elicited CD8(+) T cells, namely those recognizing the peptide 157-165 with sufficiently high functional avidity, recognized the naturally processed target on NY-ESO-1(+) tumor cells. In contrast, the majority of peptide 157-165-specific CD8(+) T cells exhibited lower functional avidity and no tumor reactivity. In addition, vaccine-elicited CD8(+) T cells specific for other overlapping epitopes in the 157-167 region failed to significantly recognize NY-ESO-1-expressing tumor targets. Thus, because of the complexity of the CD8(+) T cell repertoire that can be elicited by vaccination with synthetic peptides, a precise definition of the targeted epitope, and hence, of the corresponding peptide to be used as immunogen, is required to ensure a precise tumor targeting.