title: Association Between High-Avidity T-Cell Receptors, Induced by α-Fetoprotein-Derived Peptides, and Anti-Tumor Effects in Patients With Hepatocellular Carcinoma.
abstract: Levels of α-fetoprotein (AFP) are measured for surveillance and diagnosis of hepatocellular carcinoma (HCC). We performed a phase 1 trial to evaluate the safety and efficacy of AFP-derived peptides as an anti-tumor vaccine for patients with advanced HCC, and characterized induction of AFP-specific T-cell receptors (TCRs).
  
  
  
  We performed a prospective study of 15 patients with HCC seen at Kanazawa University Hospital in Japan from March 2010 through March 2012. Each patient was given a subcutaneous injection of 3 mg AFP-derived peptides (AFP357and AFP403) in an emulsion with incomplete Freund's adjuvant every other week for at least 6 weeks. Patients were evaluated every 8 weeks by radiologic imaging; adverse events and toxicities were categorized and graded using the common terminology criteria for adverse events. Criteria for discontinuation included unacceptable toxicities and disease progression defined as progressive disease using the Response Evaluation Criteria In Solid Tumors criteria. Patients' immune responses were monitored using an interferon-gamma enzyme-linked immunospot assay. Peptide-specific TCRs were assessed using a rapid TCR cloning and evaluation system. The observation period was 730 days. A complete response was defined as the disappearance of all tumors; stable disease was defined as tumors whose total diameter remained between >70% and <120% of the baseline measurement, without new lesions.
  
  
  
  We did not observe any serious adverse reactions to the peptides, which were well tolerated. Of the 15 patients who received at least 3 injections, 5 (33%) had an immune response to the peptides. One of the 15 patients had a complete response and disease stabilized in 8 patients. In 4 of the 15 patients, we detected AFP357-specific CD8 T cells; we cloned 14 different TCRs with different avidities for the peptide. A TCR with the highest avidity was observed in the patient who achieved a complete response for more than 2 years.
  
  
  
  In a phase 1 trial, administration of AFP-derived peptides to 15 patients with HCC did not cause adverse events and produced T cells with receptors that reacted to the peptides; 1 patient had a complete response and tumor growth slowed in 8 patients. T cells from the patient with a complete response expressed a highly functional TCR induced by the peptide vaccines. UMIN-CTR no: UMIN000003514.
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nakagawa
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan. Electronic address: eishirom@m-kanazawa.jp.
authors.forename: Eishiro
authors.initials: E
authors.lastname: Mizukoshi
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan; Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Toshikatsu
authors.initials: T
authors.lastname: Tamai
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Hamana
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Ozawa
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kitahara
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Arai
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Terashima
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Noriho
authors.initials: N
authors.lastname: Iida
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Fushimi
authors.affiliation: Department of Immunology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Muraguchi
authors.affiliation: Department of Gastroenterology, Graduate School of Medicine, Kanazawa University, Kanazawa, Ishikawa, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D019496:Cancer Vaccines / Q000009:adverse effects / Q000276:immunology / Q000627:therapeutic use*; D006528:Carcinoma, Hepatocellular / Q000000981:diagnostic imaging / Q000628:therapy*; D002470:Cell Survival; D018920:Coculture Techniques; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D007167:Immunotherapy; D007371:Interferon-gamma / Q000378:metabolism; D008113:Liver Neoplasms / Q000000981:diagnostic imaging / Q000628:therapy*; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000276:immunology*; D011446:Prospective Studies; D011948:Receptors, Antigen, T-Cell / Q000032:analysis / Q000276:immunology*; D066066:Response Evaluation Criteria in Solid Tumors; D000509:alpha-Fetoproteins / Q000276:immunology*
chemical_list: D019496:Cancer Vaccines; D010455:Peptides; D011948:Receptors, Antigen, T-Cell; D000509:alpha-Fetoproteins; D007371:Interferon-gamma
keywords: Cancer; Cytotoxic T Lymphocyte; Epitope; Immunotherapy