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Imaging-guided gene therapy of experimental gliomas


Jacobs, A H; Rueger, M A; Winkeler, A; Li, H; Vollmar, S; Waerzeggers, Y; Rueckriem, B; Kummer, C; Dittmar, C; Klein, M; Heneka, M T; Herrlinger, U; Fraefel, C; Graf, R; Wienhard, K; Heiss, W-D (2007). Imaging-guided gene therapy of experimental gliomas. Cancer Research, 67(4):1706-1715.

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 2-18F-fluoro-2- deoxy-D-glucose, methyl-11C-L-methionine, or 3¶-deoxy-3¶-18Ffluoro- L-thymidine ([18F]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 -[4-18F-fluoro-3- (hydroxymethyl)butyl]guanine ([18F]FHBG) PET. Therapeutic effects could be monitored by PET with significant differences in [18F]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 [18F]FHBG-PET correlated with therapeutic efficiency as measured by [18F]FLT-PET. These data indicate that imagingguided 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.

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 2-18F-fluoro-2- deoxy-D-glucose, methyl-11C-L-methionine, or 3¶-deoxy-3¶-18Ffluoro- L-thymidine ([18F]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 -[4-18F-fluoro-3- (hydroxymethyl)butyl]guanine ([18F]FHBG) PET. Therapeutic effects could be monitored by PET with significant differences in [18F]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 [18F]FHBG-PET correlated with therapeutic efficiency as measured by [18F]FLT-PET. These data indicate that imagingguided 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.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Virology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2007
Deposited On:23 Mar 2009 15:39
Last Modified:05 Apr 2016 12:38
Publisher:American Association for Cancer Research
ISSN:0008-5472
Publisher DOI:https://doi.org/10.1158/0008-5472.CAN-06-2418
PubMed ID:17308112

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