title: Multiepitope CD8(+) T cell response to a NY-ESO-1 peptide vaccine results in imprecise tumor targeting.
abstract: 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.
authors.affiliation: Ludwig Institute Clinical Trial Center, New York Branch at Division of Medical Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032, USA.
authors.forename: Valérie
authors.initials: V
authors.lastname: Dutoit
authors.forename: Robert N
authors.initials: RN
authors.lastname: Taub
authors.forename: Kyriakos P
authors.initials: KP
authors.lastname: Papadopoulos
authors.forename: Susan
authors.initials: S
authors.lastname: Talbot
authors.forename: Mary-Louise
authors.initials: ML
authors.lastname: Keohan
authors.forename: Michelle
authors.initials: M
authors.lastname: Brehm
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.forename: Paul E
authors.initials: PE
authors.lastname: Harris
authors.forename: Brygida
authors.initials: B
authors.lastname: Bisikirska
authors.forename: Philippe
authors.initials: P
authors.lastname: Guillaume
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Cerottini
authors.forename: Charles S
authors.initials: CS
authors.lastname: Hesdorffer
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Danila
authors.initials: D
authors.lastname: Valmori
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D000939:Epitopes / Q000276:immunology / Q000378:metabolism*; D015789:HLA-A2 Antigen / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007890:Leiomyosarcoma / Q000276:immunology / Q000628:therapy; D008297:Male; D008565:Membrane Proteins; D009369:Neoplasms / Q000276:immunology* / Q000628:therapy; D011485:Protein Binding; D011506:Proteins / Q000276:immunology*; D013584:Sarcoma, Synovial / Q000276:immunology / Q000628:therapy; D022223:Vaccines, Subunit / Q000276:immunology* / Q000627:therapeutic use
chemical_list: D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D000939:Epitopes; D015789:HLA-A2 Antigen; D008565:Membrane Proteins; D011506:Proteins; D022223:Vaccines, Subunit