[en] To further develop gene therapy for patients with glioblastomas, an experimental gene therapy protocol was established comprising a series of imaging parameters for (i) noninvasive assessment of viable target tissue followed by (ii) targeted application of herpes simplex virus type 1 (HSV-1) amplicon vectors and (iii) quantification of treatment effects by imaging. We show that viable target tissue amenable for application of gene therapy vectors can be identified by multitracer positron emission tomography (PET) using 2-(18)F-fluoro-2-deoxy-D-glucose, methyl-(11)C-L-methionine, or 3'-deoxy-3'-(18)F-fluoro-L-thymidine ([(18)F]FLT). Targeted application of HSV-1 amplicon vectors containing two therapeutic genes with synergistic antitumor activity (Escherichia coli cytosine deaminase, cd, and mutated HSV-1 thymidine kinase, tk39, fused to green fluorescent protein gene, gfp) leads to an overall response rate of 68%, with 18% complete responses and 50% partial responses. Most importantly, we show that the "tissue dose" of HSV-1 amplicon vector-mediated gene expression can be noninvasively assessed by 9-[4-(18)F-fluoro-3-(hydroxymethyl)butyl]guanine ([(18)F]FHBG) PET. Therapeutic effects could be monitored by PET with significant differences in [(18)F]FLT accumulation in all positive control tumors and 72% in vivo transduced tumors (P = 0.01) as early as 4 days after prodrug therapy. For all stably and in vivo transduced tumors, cdIREStk39gfp gene expression as measured by [(18)F]FHBG-PET correlated with therapeutic efficiency as measured by [(18)F]FLT-PET. These data indicate that imaging-guided vector application with determination of tissue dose of vector-mediated gene expression and correlation to induced therapeutic effect using multimodal imaging is feasible. This strategy will help in the development of safe and efficient gene therapy protocols for clinical application.
Disciplines :
Neurology
Author, co-author :
Jacobs, Andreas H; Laboratory for Gene Therapy and Molecular Imaging at the Max Planck Institute for Neurological Research, University of Cologne, Gleuelerstrasse 50, 50931 Cologne, Germany. Andreas.Jacobs@nf.mpg.de
Rueger, Maria Adele; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Winkeler, Alexandra; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Li, Hongfeng; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Vollmar, Stefan; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Waerzeggers, Yannic; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Rueckriem, Benedikt; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Kummer, Christiane; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Dittmar, Claus; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Klein, Markus; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
HENEKA, Michael ; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Herrlinger, Ulrich; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Fraefel, Cornel; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Graf, Rudolf; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Wienhard, Klaus; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
Heiss, Wolf-Dieter; Max Planck Institute for Neurological Research, Department of Neurology, University of Cologne, Cologne, Germany
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