• Open Access

NY-ESO-1 antigen-reactive T cell receptors exhibit diverse therapeutic capability

Authors

  • Daniel Sommermeyer,

    1. Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
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  • Heinke Conrad,

    1. Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
    2. Department of Hematology/Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Holger Krönig,

    1. Department of Hematology/Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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  • Haike Gelfort,

    1. Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
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  • Helga Bernhard,

    1. Division of Immunogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany
    2. Department of Hematology/Oncology, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
    3. Department of Hematology/Oncology, Klinikum Darmstadt GmbH, Darmstadt, Germany
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    • H.B. and W.U. equally contributed to this work.

  • Wolfgang Uckert

    Corresponding author
    1. Max-Delbrück-Center for Molecular Medicine, Berlin, Germany
    2. Institute of Biology, Humboldt University Berlin, Berlin, Germany
    • Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Straβe 10, D-13092 Berlin, Germany
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    • H.B. and W.U. equally contributed to this work.

    • Tel.: [+49-30-94063196], Fax: [+49-30-94063306]


Abstract

The cancer-testis antigen NY-ESO-1 has been used as a target for different immunotherapies like vaccinations and adoptive transfer of antigen-specific cytotoxic T cells, as it is expressed in various tumor types and has limited expression in normal cells. The in vitro generation of T cells with defined antigen specificity by T cell receptor (TCR) gene transfer is an established method to create cells for immunotherapy. However, an extensive characterization of TCR which are candidates for treatment of patients is crucial for successful therapies. The TCR has to be efficiently expressed, their affinity to the desired antigen should be high enough to recognize low amounts of endogenously processed peptides on tumor cells, and the TCR should not be cross-reactive to other antigens. We characterized three NY-ESO-1 antigen-reactive cytotoxic T lymphocyte clones which were generated by different approaches of T cell priming (autologous, allogeneic), and transferred their TCR into donor T cells for more extensive evaluations. Although one TCR most efficiently bound MHC-multimers loaded with NY-ESO-1 peptide, T cells expressing this transgenic TCR were not able to recognize endogenously processed antigen. A second TCR recognized HLA-A2 independent of the bound peptide beside its much stronger recognition of NY-ESO-1 bound to HLA-A2. A third TCR displayed an intermediate but peptide-specific performance in all functional assays and, therefore, is the most promising candidate TCR for further clinical development. Our data indicate that multiple parameters of TCR gene-modified T cells have to be evaluated to identify an optimal TCR candidate for adoptive therapy.

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