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Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment

Gene Therapy volume 17, pages 202–216 (2010)Cite this article

Abstract

The objective of the present study was to evaluate the cellular effects of the oncolytic HSV-1 based vector, G207, on the tumor microenvironment. We established progressively growing intracerebral xenografts in athymic nude rats generated from three different human GBM surgical specimens. The lesions were identified by MRI and subsequently injected with a concentrated vector stock. The animals were killed 10 or 30 days after G207 injection and the tumors were quantitatively evaluated for virus-induced changes in proliferation, apoptosis and vascularity. Moreover, we assessed vector spread as well as the infiltration pattern of CD68-positive inflammatory cells. In all G207-injected lesions, immunostaining identified widespread regions of viral infection and replication (plaques). Proliferation indices were significantly lower, whereas apoptotic counts were significantly elevated in plaques as compared with that in non-infected areas of the same lesions, as well as in corresponding control xenografts. Furthermore, there was a significant decline in the number of blood vessels in the plaques and the vascular area fractions were reduced. CD68-positive inflammatory cells accumulated in the plaques. The present study highlights the favorable cellular responses to G207 treatment seen from a clinical viewpoint, such as reduced tumor cell proliferation, more frequent events of tumor cell death and a strongly attenuated tumor vascular compartment. However, our results suggest that transduction of a significant volume of tumor tissue is essential, as these beneficial changes were only observed in areas of active viral replication, leaving non-transduced tumor tissues unaffected.

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Acknowledgements

This work was supported by the Norwegian Cancer Society, the Norwegian Research Council, Innovest AS, Helse-Vest (Regional Health Authority of Western Norway), Haukeland University Hospital, the Bergen Translational Research Program, the Centre Recherché de Public Santé Luxembourg, MediGene AG and the European Commission 6th Framework Program Contract 504743. We acknowledge Christine Eriksen, Bodil Hansen, Tove Johansen and Ingrid Gavlen for technical assistance. We thank Dr Anja Gutermann and Dr Ulrich Moebius at MediGene AG (Martinsried, Germany) for outstanding collaboration.

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Authors and Affiliations

  1. Department of Biomedicine, NorLux Neuro-oncology Laboratory, University of Bergen, Bergen, Norway

    P C Huszthy, J Wang, D Goplen, H Miletic & R Bjerkvig

  2. Helse-Vest, Haukeland University Hospital, Bergen, Norway

    P C Huszthy

  3. Section for Pathology, The Gade Institute, University of Bergen, Bergen, Norway

    H Immervoll & D Goplen

  4. Department of Pathology, Haukeland University Hospital, Bergen, Norway

    H Immervoll & H Miletic

  5. Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway

    D Goplen

  6. Centre for Clinical Research, Haukeland, University Hospital, Bergen, Norway

    G E Eide

  7. Department of Public Health and Primary Health Care, Epiforsk Research Group, University of Bergen, Bergen, Norway

    G E Eide

  8. NorLux Neuro-oncology, Centre Recherché de Public Santé, Luxembourg, Luxembourg

    R Bjerkvig

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  1. P C Huszthy
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Correspondence to P C Huszthy.

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Huszthy, P., Immervoll, H., Wang, J. et al. Cellular effects of oncolytic viral therapy on the glioblastoma microenvironment. Gene Ther 17, 202–216 (2010). https://doi.org/10.1038/gt.2009.130

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