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Targeting the epidermal growth factor receptor (HER) family by T cell receptor gene-modified T lymphocytes

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Abstract

Human epidermal growth factor receptor 2 (HER2) has been successfully targeted as a breast cancer-associated antigen by various strategies. HER2 is also overexpressed in other solid tumors such as stomach cancer, as well as in hematological malignancies such as acute lymphoblastic leukemia. HER2-targeted therapies are currently under clinical investigation for a panel of malignancies. In this study, we isolated the T cell receptor (TCR) genes of a HER2-reactive allo-human leukocyte antigen-A2-restricted CTL clone and introduced the TCRα- and β-chain genes into the retrovirus vector MP71. Murinization and codon optimization of the HER2-reactive TCR was required for efficient TCR expression in primary human T cells. The tumor recognition efficiency of HER2-TCR gene-modified T cells was similar to the parental CTL clone from which the TCR genes were isolated. The known cross-reactivity of the HER2-reactive TCR with HER3 and HER4 was retained when the TCR was transduced into primary T cells. Our results could contribute to the development of a TCR-based approach for the treatment of HER2-positive breast cancer, as well as of other malignancies expressing HER2, HER3, and/or HER4.

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Acknowledgements

This study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB-TR36 to W.U., SFB-456 to H.B. and D.H.B., DFG BE 1579/4-1 to H.B., DFG 4/6-1 to W.U.) and from the Helmholtz Alliance Immunotherapy of Cancer (to H.B. and W.U.). We thank Kordelia Hummel, Uta Fischer, Julia Müller, and Barbara Kast for excellent technical assistance and D. Schendel for critical reading of the manuscript.

Disclosure statement

P.M. and H.C. performed research, collected and analyzed data, and wrote the manuscript; L.S. and M.L. performed research; D.B. provided vital tools; and W.U. and H.B. designed and supervised research, reviewed the data, and wrote the manuscript. The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Molecular Cell Biology and Gene Therapy, Max-Delbrück-Center for Molecular Medicine, Berlin, Germany

    Peter Meyerhuber, Lilian Stärck, Matthias Leisegang & Wolfgang Uckert

  2. Institute of Immunology, Charité, Berlin, Germany

    Peter Meyerhuber

  3. Department of Hematology/Oncology, Technical University of Munich, Klinikum rechts der Isar, Munich, Germany

    Heinke Conrad & Helga Bernhard

  4. Clinical Cooperation Group ‘Antigen-Specific Immunotherapy’, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany

    Heinke Conrad, Dirk H. Busch & Helga Bernhard

  5. Institute of Microbiology, Immunology and Hygiene, Technical University of Munich, Munich, Germany

    Dirk H. Busch

  6. Institute of Biology, Humboldt-University, Berlin, Germany

    Wolfgang Uckert

  7. Department of Hematology/Oncology, Klinikum Darmstadt, Grafenstraße 9, 64293, Darmstadt, Germany

    Helga Bernhard

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  1. Peter Meyerhuber
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  2. Heinke Conrad
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  4. Matthias Leisegang
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  5. Dirk H. Busch
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  7. Helga Bernhard
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Corresponding author

Correspondence to Helga Bernhard.

Additional information

Peter Meyerhuber, Heinke Conrad, Wolfgang Uckert, and Helga Bernhard contributed equally to this work.

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Meyerhuber, P., Conrad, H., Stärck, L. et al. Targeting the epidermal growth factor receptor (HER) family by T cell receptor gene-modified T lymphocytes. J Mol Med 88, 1113–1121 (2010). https://doi.org/10.1007/s00109-010-0660-z

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  • DOI: https://doi.org/10.1007/s00109-010-0660-z

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