title: Imaging-guided gene therapy of experimental gliomas.
abstract: 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.
authors.affiliation: 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
authors.forename: Andreas H
authors.initials: AH
authors.lastname: Jacobs
authors.forename: Maria Adele
authors.initials: MA
authors.lastname: Rueger
authors.forename: Alexandra
authors.initials: A
authors.lastname: Winkeler
authors.forename: Hongfeng
authors.initials: H
authors.lastname: Li
authors.forename: Stefan
authors.initials: S
authors.lastname: Vollmar
authors.forename: Yannic
authors.initials: Y
authors.lastname: Waerzeggers
authors.forename: Benedikt
authors.initials: B
authors.lastname: Rueckriem
authors.forename: Christiane
authors.initials: C
authors.lastname: Kummer
authors.forename: Claus
authors.initials: C
authors.lastname: Dittmar
authors.forename: Markus
authors.initials: M
authors.lastname: Klein
authors.forename: Michael T
authors.initials: MT
authors.lastname: Heneka
authors.forename: Ulrich
authors.initials: U
authors.lastname: Herrlinger
authors.forename: Cornel
authors.initials: C
authors.lastname: Fraefel
authors.forename: Rudolf
authors.initials: R
authors.lastname: Graf
authors.forename: Klaus
authors.initials: K
authors.lastname: Wienhard
authors.forename: Wolf-Dieter
authors.initials: WD
authors.lastname: Heiss
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000000981:diagnostic imaging* / Q000235:genetics / Q000628:therapy*; D006801:Humans; D007091:Image Processing, Computer-Assisted / Q000379:methods; D051379:Mice; D008819:Mice, Nude; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D051381:Rats; D011923:Rats, Nude
chemical_list: D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C002854:alovudine