PMID- 26052074
OWN - NLM
STAT- MEDLINE
DCOM- 20151229
LR  - 20220408
IS  - 1528-0012 (Electronic)
IS  - 0016-5085 (Linking)
VI  - 149
IP  - 4
DP  - 2015 Oct
TI  - T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to 
      Recognize and Kill Hepatoma Cells In Vitro and in Mice.
PG  - 1042-52
LID - S0016-5085(15)00782-9 [pii]
LID - 10.1053/j.gastro.2015.05.055 [doi]
AB  - BACKGROUND & AIMS: Cancer therapies are being developed based on our ability to 
      direct T cells against tumor antigens. Glypican-3 (GPC3) is expressed by 75% of 
      all hepatocellular carcinomas (HCC), but not in healthy liver tissue or other 
      organs. We aimed to generate T cells with GPC3-specific receptors that recognize 
      HCC and used them to eliminate GPC3-expressing xenograft tumors grown from human 
      HCC cells in mice. METHODS: We used mass spectrometry to obtain a comprehensive 
      peptidome from GPC3-expressing hepatoma cells after immune-affinity purification 
      of human leukocyte antigen (HLA)-A2 and bioinformatics to identify immunodominant 
      peptides. To circumvent GPC3 tolerance resulting from fetal expression, dendritic 
      cells from HLA-A2-negative donors were cotransfected with GPC3 and HLA-A2 RNA to 
      stimulate and expand antigen-specific T cells. RESULTS: Peptide GPC3367 was 
      identified as a predominant peptide on HLA-A2. We used A2-GPC3367 multimers to 
      detect, select for, and clone GPC3-specific T cells. These clones bound the 
      A2-GPC3367 multimer and secreted interferon-gamma when cultured with GPC3367, but not 
      with control peptide-loaded cells. By genomic sequencing of these T-cell clones, 
      we identified a gene encoding a dominant T-cell receptor. The gene was cloned and 
      the sequence was codon optimized and expressed from a retroviral vector. Primary 
      CD8(+) T cells that expressed the transgenic T-cell receptor specifically bound 
      GPC3367 on HLA-A2. These T cells killed GPC3-expressing hepatoma cells in culture 
      and slowed growth of HCC xenograft tumors in mice. CONCLUSIONS: We identified a 
      GPC3367-specific T-cell receptor. Expression of this receptor by T cells allows 
      them to recognize and kill GPC3-positive hepatoma cells. This finding could be 
      used to advance development of adoptive T-cell therapy for HCC.
CI  - Copyright (c) 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.
FAU - Dargel, Christina
AU  - Dargel C
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany.
FAU - Bassani-Sternberg, Michal
AU  - Bassani-Sternberg M
AD  - Max Planck Institute of Biochemistry, Martinsried, Germany.
FAU - Hasreiter, Julia
AU  - Hasreiter J
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany.
FAU - Zani, Fabio
AU  - Zani F
AD  - Institute for Diabetes and Obesity, Helmholtz Zentrum Munchen, Garching, Germany.
FAU - Bockmann, Jan-Hendrik
AU  - Bockmann JH
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany; German Center for Infection Research (DZIF), Munich Site, 
      Germany.
FAU - Thiele, Frank
AU  - Thiele F
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany; German Center for Infection Research (DZIF), Munich Site, 
      Germany.
FAU - Bohne, Felix
AU  - Bohne F
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany.
FAU - Wisskirchen, Karin
AU  - Wisskirchen K
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany.
FAU - Wilde, Susanne
AU  - Wilde S
AD  - Institute of Molecular Immunology, Helmholtz Zentrum Munchen, Munchen, Germany.
FAU - Sprinzl, Martin F
AU  - Sprinzl MF
AD  - I. Medizinische Klinik und Poliklinik, Universitatsmedizin der Johannes 
      Gutenberg-Universitat, Mainz, Germany.
FAU - Schendel, Dolores J
AU  - Schendel DJ
AD  - Institute of Molecular Immunology, Helmholtz Zentrum Munchen, Munchen, Germany; 
      Clinical Cooperation Groups Antigen Specific Immunotherapy and Immune Monitoring, 
      Technische Universitat Munchen, Helmholtz Zentrum Munchen, Munchen, Germany.
FAU - Krackhardt, Angela M
AU  - Krackhardt AM
AD  - Clinical Cooperation Groups Antigen Specific Immunotherapy and Immune Monitoring, 
      Technische Universitat Munchen, Helmholtz Zentrum Munchen, Munchen, Germany; 3rd 
      Medical Department, University Hospital Rechts der Isar, Technische Universitat 
      Munchen, Munchen, Germany.
FAU - Uckert, Wolfgang
AU  - Uckert W
AD  - Max-Delbruck-Centrum for Molecular Medicine (MDC) and Institute of Biology, 
      Humboldt University Berlin, Berlin-Buch, Germany.
FAU - Wohlleber, Dirk
AU  - Wohlleber D
AD  - Institute of Molecular Immunology, University Hospital Rechts der Isar, 
      Technische Universitat Munchen, Munchen, Germany.
FAU - Schiemann, Matthias
AU  - Schiemann M
AD  - Clinical Cooperation Groups Antigen Specific Immunotherapy and Immune Monitoring, 
      Technische Universitat Munchen, Helmholtz Zentrum Munchen, Munchen, Germany; 
      Institute for Medical Microbiology, Immunology and Hygiene, Technische 
      Universitat Munchen, Munchen, Germany.
FAU - Stemmer, Kerstin
AU  - Stemmer K
AD  - Institute for Diabetes and Obesity, Helmholtz Zentrum Munchen, Garching, Germany.
FAU - Heikenwalder, Mathias
AU  - Heikenwalder M
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany.
FAU - Busch, Dirk H
AU  - Busch DH
AD  - German Center for Infection Research (DZIF), Munich Site, Germany; Clinical 
      Cooperation Groups Antigen Specific Immunotherapy and Immune Monitoring, 
      Technische Universitat Munchen, Helmholtz Zentrum Munchen, Munchen, Germany; 
      Institute for Medical Microbiology, Immunology and Hygiene, Technische 
      Universitat Munchen, Munchen, Germany.
FAU - Richter, Gunther
AU  - Richter G
AD  - Department of Pediatrics, University Hospital Rechts der Isar, Technische 
      Universitat Munchen, Munchen, Germany.
FAU - Mann, Matthias
AU  - Mann M
AD  - Max Planck Institute of Biochemistry, Martinsried, Germany.
FAU - Protzer, Ulrike
AU  - Protzer U
AD  - Institute of Virology, Technische Universitat Munchen, Helmholtz Zentrum Munchen, 
      Munchen, Germany; German Center for Infection Research (DZIF), Munich Site, 
      Germany; Clinical Cooperation Groups Antigen Specific Immunotherapy and Immune 
      Monitoring, Technische Universitat Munchen, Helmholtz Zentrum Munchen, Munchen, 
      Germany. Electronic address: protzer@tum.de.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20150605
PL  - United States
TA  - Gastroenterology
JT  - Gastroenterology
JID - 0374630
RN  - 0 (GPC3 protein, human)
RN  - 0 (Glypicans)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (IFNG protein, human)
RN  - 0 (Immunodominant Epitopes)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/immunology/metabolism/*transplantation
MH  - Carcinoma, Hepatocellular/genetics/immunology/metabolism/pathology/*therapy
MH  - Cell Survival
MH  - Coculture Techniques
MH  - *Cytotoxicity, Immunologic
MH  - Dendritic Cells/immunology/*metabolism
MH  - Female
MH  - *Genes, T-Cell Receptor
MH  - Genetic Engineering/*methods
MH  - Glypicans/genetics/immunology/*metabolism
MH  - HLA-A2 Antigen/genetics/immunology/*metabolism
MH  - Hep G2 Cells
MH  - Humans
MH  - Immunodominant Epitopes
MH  - Immunotherapy, Adoptive/*methods
MH  - Interferon-gamma/immunology/metabolism
MH  - Liver Neoplasms/genetics/immunology/metabolism/pathology/*therapy
MH  - *Lymphocyte Activation
MH  - Mice, SCID
MH  - Time Factors
MH  - Transfection
MH  - Xenograft Model Antitumor Assays
OTO - NOTNLM
OT  - Cancer Immunotherapy
OT  - Immune Response
OT  - Liver Cancer
OT  - Tumor-Associated Antigens
EDAT- 2015/06/09 06:00
MHDA- 2015/12/30 06:00
CRDT- 2015/06/09 06:00
PHST- 2014/10/16 00:00 [received]
PHST- 2015/05/16 00:00 [revised]
PHST- 2015/05/30 00:00 [accepted]
PHST- 2015/06/09 06:00 [entrez]
PHST- 2015/06/09 06:00 [pubmed]
PHST- 2015/12/30 06:00 [medline]
AID - S0016-5085(15)00782-9 [pii]
AID - 10.1053/j.gastro.2015.05.055 [doi]
PST - ppublish
SO  - Gastroenterology. 2015 Oct;149(4):1042-52. doi: 10.1053/j.gastro.2015.05.055. 
      Epub 2015 Jun 5.