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  • Cell-Based Therapy
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Cell-Based Therapy

Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR

Gene Therapy volume 7, pages 1369–1377 (2000)Cite this article

Abstract

Primary human activated T lymphocytes were genetically grafted with chimeric T cell receptors (TCR). Three domain single chain (sc-) TCR as well as two chain (tc-) TCR gene constructs were derived from the melanoma-specific cytotoxic human T cell (CTL) clone 82/30, and linked to the CD3-ζ signaling element. Chimeric TCR α and β receptor genes were structurally designed to prevent pairing with endogenous TCR α and β chains in order to prevent the generation of unpredictable immune specificities. After transduction of polyclonally activated human peripheral blood lymphocytes with retroviral vectors harboring the chimeric receptor genes, genetically engineered cells specifically recognized and responded to MAGE-A1POS/HLA-A1POS cells. Importantly, each type of transduced T lymphocytes that bound specifically to peptide/MHC complexes also showed specific anti-tumor reactivity as well as lymphokine production. Genetically engineered primary human T lymphocytes expressing chimeric sc- or tc-TCR therefore hold promise for disease-specific therapies.

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Acknowledgements

We thank Dr Hennie Hoogenboom, CESAME, Dept of Pathology, Maastricht University, The Netherlands, Dr Marc Bonneville, INSERM U463, Institute de Biology, Nantes, France, and Dr John Ortaldo, Dept of Experimental Immunology, NCI-FCRDC, Frederick, USA for their helpful suggestions and discussions. This work was supported by the Dutch Technology Foundation STW (project RGN44.3498), a fellowship of the Netherlands Organization for Scientific Research (NWO; R 93–244) and by the Dutch Cancer Society (Koningin Wilhelmina Fonds; project 92–115).

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Authors and Affiliations

  1. Department of Clinical and Tumor Immunology, Academic Hospital Rotterdam/Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

    R A Willemsen, M E M Weijtens, C Ronteltap, J W Gratama & R L H Bolhuis

  2. Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel

    Z Eshhar

  3. Department of Pathology, Academic Hospital Maastricht, Maastricht, The Netherlands

    P Chames

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  1. R A Willemsen
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  7. R L H Bolhuis
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Willemsen, R., Weijtens, M., Ronteltap, C. et al. Grafting primary human T lymphocytes with cancer-specific chimeric single chain and two chain TCR. Gene Ther 7, 1369–1377 (2000). https://doi.org/10.1038/sj.gt.3301253

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