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  T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to Recognize and Kill Hepatoma Cells In Vitro and in Mice

Dargel, C., Bassani-Sternberg, M., Hasreiter, J., Zani, F., Bockmann, J.-H., Thiele, F., et al. (2015). T Cells Engineered to Express a T-Cell Receptor Specific for Glypican-3 to Recognize and Kill Hepatoma Cells In Vitro and in Mice. GASTROENTEROLOGY, 149(4), 1042-1052. doi:10.1053/j.gastro.2015.05.055.

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Dargel, Christina1, Author
Bassani-Sternberg, Michal2, Author              
Hasreiter, Julia1, Author
Zani, Fabio1, Author
Bockmann, Jan-Hendrik1, Author
Thiele, Frank1, Author
Bohne, Felix1, Author
Wisskirchen, Karin1, Author
Wilde, Susanne1, Author
Sprinz, Martin F.1, Author
Schende, Dolores J.1, Author
Krackhardt, Angela M.1, Author
Uckert, Wolfgang1, Author
Wohlleber, Dirk1, Author
Schiemann, Matthias1, Author
Stemmer, Kerstin1, Author
Heikenwaelder, Mathias1, Author
Busch, Dirk H.1, Author
Richter, Guenther1, Author
Mann, Matthias2, Author              
Protzer, Ulrike1, Author more..
Affiliations:
1external, ou_persistent22              
2Mann, Matthias / Proteomics and Signal Transduction, Max Planck Institute of Biochemistry, Max Planck Society, ou_1565159              

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Free keywords: HEPATOCELLULAR-CARCINOMA; DENDRITIC CELLS; LYMPHOCYTES; ANTIGEN; IMMUNOTHERAPY; PROGNOSIS; PEPTIDES; EPITOPES; EFFICACY; THERAPYCancer Immunotherapy; Tumor-Associated Antigens; Liver Cancer; Immune Response;
 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 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 cotrans-fected with GPC3 and HLA-A2 RNA to stimulate and expand antigen-specific T cells. RESULTS: Peptide GPC3(367) was identified as a predominant peptide on HLA-A2. We used A2-GPC3(367) multimers to detect, select for, and clone GPC3-specific T cells. These clones bound the A2-GPC3(367) multimer and secreted interferon-g when cultured with GPC3(367), 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 GPC3(367) 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 GPC3(367)-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.

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Language(s): eng - English
 Dates: 2015
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Degree: -

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Title: GASTROENTEROLOGY
Source Genre: Journal
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Publ. Info: 1600 JOHN F KENNEDY BOULEVARD, STE 1800, PHILADELPHIA, PA 19103-2899 USA : W B SAUNDERS CO-ELSEVIER INC
Pages: - Volume / Issue: 149 (4) Sequence Number: - Start / End Page: 1042 - 1052 Identifier: ISSN: 0016-5085