© 2005 by the Society forNeuro-Oncology
Increased efficacy of an interleukin-12-secreting herpes simplex virus ina syngeneic intracranial murine glioma model
Brain Tumor Research Laboratories, Division ofNeurosurgery, Department of Surgery (E.K.H., J.M.M., C.P.L., S.B., G.Y.G.),and Division of Clinical Virology, Department ofPediatrics (J.N.P., R.J.W.), University of Alabama School of Medicine,Birmingham AL 35294, USA; Marjorie B. Kovler ViralOncology Laboratories, University of Chicago, Chicago, IL 60637, USA (B.H.,B.R.); University of Illinois, Chicago, IL 60612, USA(B.H.); Laboratoire d'Oncologie Virale etMoléculaire, Institut Curie, 91405 Orsay, France (B.P.)
2 Address correspondence to G. Yancey Gillespie, Division of Neurosurgery, 1032THT, University of Alabama at Birmingham, 1530 3rd Avenue, South, Birmingham,AL 35294-0006, USA(yancey{at}uab.edu).
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Abstract |
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Long-term survivors of glioblastoma multiforme, the most common form ofprimary intracranial malignancy in adults, are extremely rare. Experimentalanimal models that more closely resemble human disease are essential for theidentification of effective novel therapies. We report here an extensiveanalysis of the 4C8 glioma model to assess its suitability for evaluatingnovel type 1 herpes simplex virus (HSV-1) therapies of malignant glioma. Wefirst determined that expression of major histocompatibility complex I and IIand of 
vβ3 in the 4C8 model was comparableto that seen in human glioma cells. Next, using a panel of
134.5 HSVs, we demonstrated that, in vitro,4C8 cells were as sensitive as human glioma cells to both infection and lysisand that the 4C8 cells supported the production of foreign gene products.Replication competence of HSV was demonstrated in vitro. Finally, 4C8intracranial gliomas were established in immunologically competent syngeneicB6D2F1 mice, treated by intratumoral injection of selectedengineered HSVs, including the interleukin-12-expressing virus, M002. Survivaldata from these studies demonstrated that 4C8 cells in vivo are sensitive toboth direct oncolysis and HSV-mediated interleukin-12 expression.Fluorescence-activated cell sorting analyses of immune-related infiltratingcells supported the concept that survival was prolonged in part because ofantitumor actions of these cells. We conclude that the 4C8/B6D2F1syngeneic glioma model is suitable for preclinical evaluation of HSV-basedtherapies and that M002 is a superior virus for the treatment of murine gliomain this model.
Received April 2, 2004; Accepted January 24, 2005
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