title: HLA-A2 and -A24-restricted glypican-3-derived peptide vaccine induces specific CTLs: preclinical study using mice.
abstract: We previously reported that glypican-3 (GPC3) is uniquely overexpressed in human hepatocellular carcinoma and melanoma and that it is an ideal tumor antigen for immunotherapy in mouse models. We recently identified both HLA-A24 (A*2402) and H-2Kd-restricted GPC3298-306 (EYILSLEEL) and HLA-A2 (A*0201)-restricted GPC3144-152 (FVGEFFTDV), both of which can induce GPC3-reactive cytotoxic T cells (CTLs). The present study was a preclinical study in a mouse model that was conducted in order to design an optimal schedule for clinical trial of GPC3-derived peptide vaccine. When BALB/c mice were intradermally vaccinated at the base of the tail with Kd-restricted GPC3298-306 peptide mixed with incomplete Freund's adjuvant (IFA), the peptide-specific CTLs were induced. But the peptide alone could not induce peptide-specific CD8+ T cells. Furthermore, proteomic analyses showed that IFA protected the peptide against degradation in the human serum. Peptide-reactive CTLs were induced by peptide vaccine in a dose-dependent manner. In addition, at least two vaccinations with a single dose >10 microg were needed for the induction of GPC3298-306-specific CTLs. But repeated vaccination with a lower dose of GPC3298-306 did not induce peptide-specific CTLs. Similarly, induction of an Ag-specific immune response by HLA-A2 GPC3144-152 depended on the dose administered. The results of this study suggested that IFA is one of the indispensable adjuvants for peptide-based immunotherapy, and that the immunological effect of peptide vaccines depends on the dose of peptide injected.
authors.affiliation: Cancer Immunotherapy Project, Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa 277-8577, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Motomura
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ikuta
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Kuronuma
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Komori
authors.forename: Masaaki
authors.initials: M
authors.lastname: Ito
authors.forename: Masami
authors.initials: M
authors.lastname: Tsuchihara
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsunoda
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Hideo
authors.initials: H
authors.lastname: Baba
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
authors.forename: Taira
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D004306:Dose-Response Relationship, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D053673:Glypicans / Q000008:administration & dosage / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology*; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology*; D059871:HLA-A24 Antigen; D006801:Humans; D007111:Immunity, Cellular / Q000187:drug effects; D007115:Immunization Schedule; D007271:Injections, Intradermal; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009842:Oligopeptides / Q000008:administration & dosage / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014162:Transfection; D022223:Vaccines, Subunit / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D018984:Epitopes, T-Lymphocyte; D053673:Glypicans; D015234:HLA-A Antigens; D015789:HLA-A2 Antigen; D059871:HLA-A24 Antigen; D009842:Oligopeptides; D022223:Vaccines, Subunit; D005620:Freund's Adjuvant