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Induced transgene expression for the treatment of solid tumors by hematopoietic stem cell-based gene therapy

Cancer Gene Therapy volume 19, pages 352–357 (2012)Cite this article

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Abstract

Tumor microenvironment is composed of different cell types including immune cells. Far from acting to eradicate cancer cells, these bone marrow-derived components could be involved in carcinogenesis and/or tumor invasion and metastasis. Here, we describe an alternative approach to treat solid tumors based on the genetic modification of hematopoietic stem and progenitor cells with lentiviral vectors. To achieve transgene expression in derivative tumor infiltrating leukocytes and to try to decrease systemic toxicity, we used the stress inducible human HSP70B promoter. Functionality of the promoter was characterized in vitro using hyperthermia. Antitumor efficacy was assessed by ex vivo genetic modification of lineage-negative cells with lentiviral vectors encoding the dominant-negative mutant of the human transforming growth factor-β receptor II (TβRIIDN) driven by the HSP70B promoter, and reinfusion of cells into recipient mice. Subsequently, syngeneic GL261 glioma cells were subcutaneously injected into bone marrow-transplanted mice. As a result, a massive antitumor response was observed in mice harboring TβRIIDN under the HSP70B promoter, without the need of any external source of stress. In summary, this study shows that stem cell-based gene therapy in combination with spatial and temporal control of transgene expression in derivative tumor-infiltrating cells represents an alternative strategy for the development of novel antitumor therapies.

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Acknowledgements

This work was supported by a project grant of the Deutsche Krebshilfe to CK and RD. This study has been approved by the Hannover Medical School Animal Care Committee.

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Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    F Noyan, I Avedillo Díez, M Hapke, C Klein & R A Dewey

  2. Instituto de Investigaciones Biotecnológicas-Instituto Tecnológico de Chascomús, (IIB-INTECH), CONICET/UNSAM, Buenos Aires, Argentina

    I Avedillo Díez & R A Dewey

Authors
  1. F Noyan
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  2. I Avedillo Díez
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  3. M Hapke
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  4. C Klein
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Correspondence to R A Dewey.

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Supplementary Information accompanies the paper on Cancer Gene Therapy website

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Noyan, F., Díez, I., Hapke, M. et al. Induced transgene expression for the treatment of solid tumors by hematopoietic stem cell-based gene therapy. Cancer Gene Ther 19, 352–357 (2012). https://doi.org/10.1038/cgt.2012.8

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  • DOI: https://doi.org/10.1038/cgt.2012.8

Keywords

  • HSP70B promoter
  • self inactivating lentiviral vectors
  • TGF-beta receptor II dominant negative mutant
  • TβRIIDN

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