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Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA × anti-CD3 diabodies from lentivirally transduced human lymphocytes

Cancer Gene Therapy volume 14, pages 380–388 (2007)Cite this article

Abstract

Infiltrating T lymphocytes are found in many malignancies, but they appear to be mostly anergic and do not attack the tumor, presumably because of defective T-cell activation events. Recently, we described a strategy for the tumor-specific polyclonal activation of tumor-resident T lymphocytes based on the in situ production of recombinant bispecific antibodies (bsAbs) by transfected nonhematological cell lines. Here, we have constructed a novel HIV-1-based lentiviral vector for efficient gene transduction into various human hematopoietic cell types. Several myelomonocytic and lymphocytic cell lines secreted the anti-carcinoembryonic antigen (CEA) × anti-CD3 diabody in a functionally active form with CD3+ T-cell lines being the most efficient secretors. Furthermore, primary human peripheral blood lymphocytes (PBLs) were also efficiently transduced and secreted high levels of functional diabody. Importantly gene-modified PBLs significantly reduced in vivo tumor growth rates in xenograft studies. These results demonstrate, for the first time, the utility of lentiviral vectors for sustained expression of recombinant bsAbs in human T lymphocytes. Such T lymphocytes, transduced ex vivo to secrete the activating diabody in autocrine fashion, may provide a promising route for a gene therapy strategy for solid human tumors.

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Acknowledgements

We thank Eduardo Martinez-Naves (Universidad Complutense de Madrid), Rosario de Pablo (Hospital Universitario Puerta de Hierro) and Didier Trono (University of Geneva) for providing reagents, and Isabel Millán (Hospital Universitario Puerta de Hierro) for statistical analysis. This work was supported by grants from the Fondo de Investigación Sanitaria (02/1144), the Comunidad Autónoma de Madrid (GR/SAL/0214/2004) and the Ministerio de Educación y Ciencia (BIO2005-04794) to LA-V. BB was supported by a Comunidad Autónoma de Madrid training grant 01/0369/2000. LS is investigator from the Ramon y Cajal Program (Ministerio de Educación y Ciencia).

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Authors and Affiliations

  1. Molecular Immunology Unit, Hospital Universitario Puerta de Hierro, Madrid, Spain

    M Compte, B Blanco, Á M Cuesta, L Sanz & L Álvarez-Vallina

  2. Tissue Bioengineering Multidisciplinary Unit, Fundación Hospital de Alcorcón, Madrid, Spain

    F Serrano

  3. Department of Immunology and Oncology, Centro Nacional de Biotecnología, Madrid, Spain

    A Bernad

  4. Medical Research Council Laboratory of Molecular Biology, Cambridge, UK

    P Holliger

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  1. M Compte
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  2. B Blanco
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  6. A Bernad
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  7. P Holliger
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  8. L Álvarez-Vallina
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Correspondence to L Álvarez-Vallina.

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Compte, M., Blanco, B., Serrano, F. et al. Inhibition of tumor growth in vivo by in situ secretion of bispecific anti-CEA × anti-CD3 diabodies from lentivirally transduced human lymphocytes. Cancer Gene Ther 14, 380–388 (2007). https://doi.org/10.1038/sj.cgt.7701021

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