Imaging-guided gene therapy of experimental gliomas.
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.
Jacobs
Andreas H
AH
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
MA
Winkeler
Alexandra
A
Li
Hongfeng
H
Vollmar
Stefan
S
Waerzeggers
Yannic
Y
Rueckriem
Benedikt
B
Kummer
Christiane
C
Dittmar
Claus
C
Klein
Markus
M
Heneka
Michael T
MT
Herrlinger
Ulrich
U
Fraefel
Cornel
C
Graf
Rudolf
R
Wienhard
Klaus
K
Heiss
Wolf-Dieter
WD
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
D015224:Dideoxynucleosides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; C002854:alovudine