title: Identification of HLA-A2- or HLA-A24-restricted CTL epitopes possibly useful for glypican-3-specific immunotherapy of hepatocellular carcinoma.
abstract: OBJECTIVE
  We previously reported that glypican-3 (GPC3) was overexpressed, specifically in hepatocellular carcinoma (HCC) and melanoma in humans, and it was useful as a novel tumor marker. We also reported that the preimmunization of BALB/c mice with dendritic cells pulsed with the H-2K(d)-restricted mouse GPC3(298-306) (EYILSLEEL) peptide prevented the growth of tumor-expressing mouse GPC3. Because of similarities in the peptide binding motifs between H-2K(d) and HLA-A24 (A*2402), the GPC3(298-306) peptide therefore seemed to be useful for the immunotherapy of HLA-A24+ patients with HCC and melanoma. In this report, we investigated whether the GPC3(298-306) peptide could induce GPC3-reactive CTLs from the peripheral blood mononuclear cells (PBMC) of HLA-A24 (A*2402)+ HCC patients. In addition, we used HLA-A2.1 (HHD) transgenic mice to identify the HLA-A2 (A*0201)-restricted GPC3 epitopes to expand the applications of GPC3-based immunotherapy to the HLA-A2+ HCC patients.
  
  
  RESULTS
  We found that the GPC3(144-152) (FVGEFFTDV) peptide could induce peptide-reactive CTLs in HLA-A2.1 (HHD) transgenic mice without inducing autoimmunity. In five out of eight HLA-A2+ GPC3+ HCC patients, the GPC3(144-152) peptide-reactive CTLs were generated from PBMCs by in vitro stimulation with the peptide and the GPC3(298-306) peptide-reactive CTLs were also generated from PBMCs in four of six HLA-A24+ GPC3+ HCC patients. The inoculation of these CTLs reduced the human HCC tumor mass implanted into nonobese diabetic/severe combined immunodeficiency mice.
  
  
  CONCLUSIONS
  Our study raises the possibility that these GPC3 peptides may therefore be applicable to cancer immunotherapy for a large number of HCC patients.
authors: Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, Honjo, Japan.
authors: Hiroyuki
authors: H
authors: Komori
authors: Tetsuya
authors: T
authors: Nakatsura
authors: Satoru
authors: S
authors: Senju
authors: Yoshihiro
authors: Y
authors: Yoshitake
authors: Yutaka
authors: Y
authors: Motomura
authors: Yoshiaki
authors: Y
authors: Ikuta
authors: Daiki
authors: D
authors: Fukuma
authors: Kazunori
authors: K
authors: Yokomine
authors: Michiko
authors: M
authors: Harao
authors: Toru
authors: T
authors: Beppu
authors: Masanori
authors: M
authors: Matsui
authors: Toshihiko
authors: T
authors: Torigoe
authors: Noriyuki
authors: N
authors: Sato
authors: Hideo
authors: H
authors: Baba
authors: Yasuharu
authors: Y
authors: Nishimura