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Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials

Nature Medicine volume 5, pages 1256–1263 (1999)Cite this article

Abstract

The long-term consequences of adenovirus-mediated conditional cytotoxic gene therapy for gliomas remain uncharacterized. We report here detection of active brain inflammation 3 months after successful inhibition of syngeneic glioma growth. The inflammatory infiltrate consisted of activated macrophages/microglia and astrocytes, and T lymphocytes positive for leucosyalin, CD3 and CD8, and included secondary demyelination. We detected strong widespread herpes simplex virus 1 thymidine kinase immunoreactivity and vector genomes throughout large areas of the brain. Thus, patient evaluation and the design of clinical trials in ongoing and future gene therapy for brain glioblastoma must address not only tumor-killing efficiency, but also long-term active brain inflammation, loss of myelin fibers and persistent transgene expression.

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Figure 1: Survival analysis.
Figure 2: Brain inflammation in long-term survivors of suicide-gene therapy.
Figure 3: Loss of myelinated fibers, HSV-1-TK immunoreactivity and macrophage and lymphocyte infiltration of perivascular cuffs.
Figure 4: Persistence of HSV-1-TK within neurons in long-term survivors of suicide-gene therapy.
Figure 5: PCR analysis of brain sections from long-term survivors of suicide-gene therapy.
Figure 6: Immune-mediated elimination of CNS-1 cells does not lead to chronic persistent infiltration of CD4+ or CD8+ T cells.
Figure 7: Injection of RAd-128 followed by ganciclovir leads to chronic sustained infiltration of CD8+ T cells.

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Acknowledgements

The technical assistance of T. Maleniak and the secretarial help of Ros Poulton, are acknowledged. We also thank I. Miller and T. Bentley from the Electron Microscopy, Photography and Graphics Unit (School of Biological Sciences, University of Manchester) for their help and advice with the final production of the figures. Comments on the work and manuscript by D. Mann, and P. Kingston are acknowledged. This work was supported by Cancer Research Campaign, UK (project grant number SP2332/0101 to P.R.L. and M.G.C.), and European Community Biomed II grant to P.R.L., M.G.C. and D.K. (Contract number BMH4-CT96-1436). T.D.S. is an Action Research Training Fellow, and P.R.L. is a Research Fellow of The Lister Institute of Preventive Medicine.

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Author notes

  1. R. A. Dewey

    Present address: Department of Neuropathology, Institute of Psychiatry, Kings College London, DeCrespigny Park, Denmark Hill, London, SE5 8AS, UK

  2. R. A. Dewey, G. Morrissey and C. M. Cowsill: R.A.D., G.M. and C.M.C. contributed equally to this study.

Authors and Affiliations

  1. Molecular Medicine and Gene Therapy Unit, Room 1.302 Stopford Building, School of Medicine,University of Manchester, Oxford Road, Manchester, M13 9PT, UK

    G. Morrissey, C. M. Cowsill, D. Stone, F. Bolognani, T. D. Southgate, M.G. Castro & P.R. Löwenstein

  2. Department of Medical Biophysics, Stopford Building University of Manchester, Oxford Road, Manchester , M13 9PT, UK

    N.J.F. Dodd

  3. Laboratoire de Biologie et Therapeutique des Pathologies Immunitaires, Universitè Pierre et Marie Curie, CNRS, Hôpital de la Pitiè-Salpétrière, 83 Boulevard de l'Hôpital, Paris, 75651 Cedex 13, France

    D. Klatzmann

  4. Neurological Institute, University of Vienna, Schwarzspanierstrasse 17, Vienna, A-1090, Austria

    H. Lassmann

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Dewey, R., Morrissey, G., Cowsill, C. et al. Chronic brain inflammation and persistent herpes simplex virus 1 thymidine kinase expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy: Implications for clinical trials. Nat Med 5, 1256–1263 (1999). https://doi.org/10.1038/15207

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