title: Phase I trial of a glypican-3-derived peptide vaccine for advanced hepatocellular carcinoma: immunologic evidence and potential for improving overall survival.
abstract: OBJECTIVE
  The carcinoembryonic antigen glypican-3 (GPC3) is an ideal target of anticancer immunotherapy against hepatocellular carcinoma (HCC). In this nonrandomized, open-label, phase I clinical trial, we analyzed the safety and efficacy of GPC3 peptide vaccination in patients with advanced HCC.
  
  
  METHODS
  Thirty-three patients with advanced HCC underwent GPC3 peptide vaccination (intradermal injections on days 1, 15, and 29 with dose escalation). The primary endpoint was the safety of GPC3 peptide vaccination. The secondary endpoints were immune response, as measured by IFN-γ ELISPOT assay, and the clinical outcomes tumor response, time to tumor progression, and overall survival (OS).
  
  
  RESULTS
  GPC3 vaccination was well-tolerated. One patient showed a partial response, and 19 patients showed stable disease 2 months after initiation of treatment. Four of the 19 patients with stable disease had tumor necrosis or regression that did not meet the criteria for a partial response. Levels of the tumor markers α-fetoprotein and/or des-γ-carboxy prothrombin temporarily decreased in nine patients. The GPC3 peptide vaccine induced a GPC3-specific CTL response in 30 patients. Furthermore, GPC3-specific CTL frequency after vaccination correlated with OS. OS was significantly longer in patients with high GPC3-specific CTL frequencies (N = 15) than in those with low frequencies (N = 18; P = 0.033).
  
  
  CONCLUSIONS
  GPC3-derived peptide vaccination was well-tolerated, and measurable immune responses and antitumor efficacy were noted. This is the first study to show that peptide-specific CTL frequency can be a predictive marker of OS in patients with HCC receiving peptide vaccination.
authors.affiliation: Section for Cancer Immunotherapy, Investigative Treatment Division, Research Center for Innovative Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan.
authors.forename: Yu
authors.initials: Y
authors.lastname: Sawada
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Yoshikawa
authors.forename: Daisuke
authors.initials: D
authors.lastname: Nobuoka
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shirakawa
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Kuronuma
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Motomura
authors.forename: Shoichi
authors.initials: S
authors.lastname: Mizuno
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ishii
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakachi
authors.forename: Masaru
authors.initials: M
authors.lastname: Konishi
authors.forename: Toshio
authors.initials: T
authors.lastname: Nakagohri
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Takahashi
authors.forename: Naoto
authors.initials: N
authors.lastname: Gotohda
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takayama
authors.forename: Kenji
authors.initials: K
authors.lastname: Yamao
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Uesaka
authors.forename: Junji
authors.initials: J
authors.lastname: Furuse
authors.forename: Taira
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakatsura
mesh_terms: D000328:Adult; D000368:Aged; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D005260:Female; D053673:Glypicans / Q000276:immunology*; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D016896:Treatment Outcome
chemical_list: D019496:Cancer Vaccines; C105937:GPC3 protein, human; D053673:Glypicans