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T cells engineered to express a T-cell receptor specific for glypican-3 recognize and kill hepatoma cells in vitro and in mice

Official URL:https://doi.org/10.1053/j.gastro.2015.05.055
PubMed:View item in PubMed
Creators Name:Dargel, C. and Bassani-Sternberg, M. and Hasreiter, J. and Zani, F. and Bockmann, J.H. and Thiele, F. and Bohne, F. and Wisskirchen, K. and Wilde, S. and Sprinzl, M.F. and Schendel, D.J. and Krackhardt, A.M. and Uckert, W. and Wohlleber, D. and Schiemann, M. and Stemmer, K. and Heikenwaelder, M. and Busch, D.H. and Richter, G. and Mann, M. and Protzer, U.
Journal Title:Gastroenterology
Journal Abbreviation:Gastroenterology
Volume:149
Number:4
Page Range:1042-1052
Date:October 2015
Keywords:Cancer Immunotherapy, Tumor-Associated Antigens, Liver Cancer, Immune Response, Animals, Mice
Abstract: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 and to obtain a comprehensive peptidome from GPC3-expressing hepatoma cells after immune-affinity purification of HLA-A2, and used bioinformatics to identify immunodominant peptides. To circumvent GPC3-tolerance resulting from fetal expression, dendritic cells from HLA-A2 negative donors were co-transfected 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, 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. CONCLUSION: 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.
ISSN:0016-5085
Publisher:Elsevier / Saunders (U.S.A.)
Item Type:Article

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