PuSH - Publikationsserver des Helmholtz Zentrums München: T cells engineered to express a T-cell receptor specific for glypican-3 to recognize and kill hepatoma cells <em>in vitro</em> and in mice.

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Dargel, C. ; Bassani-Sternberg, M.* ; Hasreiter, J. ; Zani, F. ; Bockmann, J.H. ; Thiele, F. ; Bohne, F. ; Wisskirchen, K. ; Wilde, S. ; Sprinzl, M.F.* ; Schendel, D.J. ; Krackhardt, A.M. ; Uckert, W.* ; Wohlleber, D.* ; Schiemann, M. ; Stemmer, K. ; Heikenwälder, M. ; Busch, D.H. ; Richter, G.* ; Mann, M.* ; Protzer, U.

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, 1042-1052 (2015)

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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-γ 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.

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