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Imaging-Guided Gene Therapy of Experimental Gliomas

Imaging-Guided Gene Therapy of Experimental Gliomas,Andreas H. Jacobs,Maria Adele Rueger,Alexandra Winkeler,Hongfeng Li,Stefan Vollmar,Yannic Waerzegg

Imaging-Guided Gene Therapy of Experimental Gliomas   (Citations: 13)
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Andreas H. Jacobs, Maria Adele Rueger, Alexandra Winkeler, Hongfeng Li, Stefan Vollmar, Yannic Waerzeggers, Benedikt Rueckriem, Christiane Kummer, Claus Dittmar, Markus Klein, Michael T. Heneka, Ulrich Herrlingerhttp://academic.research.microsoft.com/io.ashx?type=5&id=5582041&selfId1=0&selfId2=0&maxNumber=12&query=
To further develop gene therapy for patients with glioblasto- mas, 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 imag- ing. We show that viable target tissue amenable for applica- tion 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¶-18F- fluoro-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 9-(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 mea- sured by (18F)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. (Cancer Res 2007;67(4):1706-15)
Published in 2007.
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    • ...In an experimental glioma model the efficacy of this treatment strategy with transfer of Herpes virus thymidine kinase gene and application of gancyclovir was demonstrated; preliminary clinical tests also showed some efficacy of this treatment option [18]...

    Heinz-Peter Schlemmeret al. An integrated MR/PET system: prospective applications

    • ...To assess the effects of therapy on tumor proliferation, 18 F-FLT imaging [22] was...

    Qizhen Caoet al. Evaluation of biodistribution and anti-tumor effect of a dimeric RGD p...

    • ...Moreover, imaging is being used to further develop new gene– and cell-based therapies [5,6]...
    • ...Imaging inducible HSV-1 amplicon vector-mediated gene expression in vivo by PET To investigate inducible HSV-1-tk39 gene expression in vivo by PET, subcutaneous human Gli36DEGFR gliomas grown in nude mice were infected with HSV-Switch-TG17 or HET6C-tk39 employing imaging-guided vector administration [6]...
    • ...The levels of TK expression as measured as %ID/g tissue were found to be within the range of values obtained with tumors infected with HSV-1 amplicon vectors expressing the viral thymidine kinase under control of a constitutive promoter [6,34]...
    • ...(i) Tumor model and imaging-guided vector application in vivo To study HSV-1 amplicon vector-mediated tk gene expression in vivo, subcutaneous Gli36DEGFR tumors, vector application and PET imaging were performed as described previously [6,34]...
    • ...(300 mCi/mouse). To study tracer accumulation and wash out, PET imaging was performed as described previously [6,34]...
    • ...To validate images of induced gene expression, animals were sacrificed after imaging and tumors were processed as described previously [6,34]...

    Alexandra Winkeleret al. Switching on the Lights for Gene Therapy

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