title: Identification of glypican-3-derived long peptides activating both CD8+and CD4+T cells; prolonged overall survival in cancer patients with Th cell response.
abstract: In a recent phase I clinical trial, a vaccine consisting of glypican-3 (GPC3)-derived CTL epitopes was found to be safe and induced measurable immune and clinical responses in patients with hepatocellular carcinoma (HCC). The aim of this study was to identify GPC3-derived long peptides (GPC3-LPs) carrying promiscuous HLA class II-restricted T helper (Th) cell epitopes. Using a computer algorithm, we predicted GPC3-LPs that can bind to promiscuous HLA class II molecules. Their antigenicity for induction of specific CD4+T cells in healthy donors or patients with HCC, before and after vaccination with GPC3-SPs, was proven by IFNγ enzyme-linked immunospot assays. Natural processing of these epitopes was confirmed by the immune response of helper T cells to dendritic cells (DCs) loaded with GPC3 proteins. Cross-presentation capacity was assessedin vitrousing human DCs and LPs encapsulated in liposomes andin vivoin HLA-A2 transgenic mice (Tgm). All five LPs could induce Th1 cells and were presented by several frequently occurring HLA class II moleculesin vitro. Four of them were likely to be naturally processed. One of the LPs encapsulated in liposomes was well cross-presentedin vitro; it cross-primed CTLs in HLA-A2 Tgm. LP-specific and HLA class II-restricted CD4+T-cell responses were observed in 14 of 20 HCC patients vaccinated with GPC3-SPs. Repeated vaccinations enhanced GPC3-LP-specific responses in 8 of 13 patients with HCC. Moreover, the presence of the specific Th cell was correlated with prolonged overall survival (OS). GPC3-LPs can be useful for cancer immunotherapy.
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Biotechnology and Genetic Engineering; Mawlana Bhashani Science and Technology University; Tangail, Bangladesh.
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Sayem
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Respiratory Medicine; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Tomita
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Oral and Maxillofacial Surgery; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Yuno
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan; Department of Oral and Maxillofacial Surgery; Graduate School of Medical Sciences; Kumamoto University; Kumamoto, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hirayama
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Irie
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan.
authors.forename: Hirotake
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Senju
authors.affiliation: Department of Applied Chemistry; Graduate School of Engineering; Osaka Prefecture University ; Sakai, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Yuba
authors.affiliation: Division of Cancer Immunotherapy; Exploratory Oncology Research and Clinical Trial Center; National Cancer Center ; Kashiwa, Japan.
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Applied Chemistry; Graduate School of Engineering; Osaka Prefecture University ; Sakai, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Kono
authors.affiliation: Division of Cancer Immunotherapy; Exploratory Oncology Research and Clinical Trial Center; National Cancer Center ; Kashiwa, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
authors.affiliation: Department of Immunogenetics; Graduate School of Medical Sciences; Kumamoto University ; Kumamoto, Japan.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Nishimura
keywords: CD4+ T cell; Cancer immunotherapy; Glypican-3; Hepatocellular carcinoma; T-cell epitope