Positron Emission Tomography Imaging of Adenoviral-Mediated Transgene Expression in Liver Cancer Patients

doi:10.1053/j.gastro.2005.03.024

Gastroenterology

Volume 128, Issue 7, June 2005, Pages 1787-1795

https://doi.org/10.1053/j.gastro.2005.03.024 Get rights and content

Background & Aims: In gene-therapy protocols, imaging of gene expression is needed to evaluate the transduction efficiency of the vector, its tissue distribution, and the duration of transgene expression and to assess the feasibility of repeated vector administration. Methods: We have used positron emission tomography with a fluorine-18-labeled penciclovir analogue to monitor thymidine kinase gene expression after intratumoral injection of a first-generation recombinant adenovirus in patients with hepatocellular carcinoma. Patients were enrolled in a pilot clinical trial and treated with escalating doses of the vector. Two days after adenovirus inoculation, transgene expression was evaluated during the first hours after administration of the radiotracer both on the treated lesion and on a whole-body basis. Results: Transgene expression in the tumor was dependent on the injected dose of the adenovirus and was detectable in all patients who received ≥10¹² viral particles. However, when the study was repeated 9 days after vector injection, no expression could be observed. It is interesting to note that no specific expression of the transgene could be detected in distant organs or in the surrounding cirrhotic tissue in any of the cases studied. Conclusions: Our findings show the real possibility of imaging transgene expression in humans by using viral vectors. We show that hepatocarcinoma is a permissive tumor for adenoviral infection and that the nontumoral cirrhotic liver is spared from transduction when the vector is administered by intratumoral injection. These results show that positron emission tomography imaging may help in the design of gene-therapy strategies and in the clinical assessment of new-generation vectors.

Section snippets

Patients and Study Design

Patients were enrolled in a phase I clinical trial externally monitored by an independent contract research organization. Permissions were obtained from the institutional review board, the Local Government’s Ethical Committee for Clinical Investigation, the National Biosafety Commission, and the Spanish Agency for the Evaluation of Medicinal Products. Informed consent was obtained from each patient before enrollment. Treatments were performed at the Liver Unit, Clínica Universitaria de Navarra

Results

AdCMVtk was administered to different groups of patients in a dose-escalation fashion in consecutive cohorts (Table 1). Contrary to patients treated with lower doses, those who received more than 10¹² vp showed no tumor progression at day 30 (Table 1), and, in fact, in 2 of 4 patients, wide areas of tumor necrosis were apparent on the CT scan performed 4 weeks after therapy. We performed a total of 36 [¹⁸F]FHBG-PET or [¹⁸F]FHBG-PET-CT studies.

Discussion

PET has been used for imaging transgene expression in animals,22, 23, 24 showing the feasibility of noninvasive quantitative evaluation of gene expression by the combination of the appropriate PET reporter gene and PET reporter probe. Many rodent studies with the FHBG tracer have been performed by our group and others (see review²⁵ and references therein). These have included transgenic models in which the liver expresses HSV1-tk driven by the albumin promoter,²⁶ studies of adenoviral-mediated

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: Supported in part by grants PI-24/2002-01 (I.P.) and 2003–04 (G.M.) from Departamento de Educación, Gobierno de Navarra, and PI 031253 (G.M.) from Fondo de Investigaciones Sanitarias. The work was also supported with funds from Plan de Investigación de la Universidad de Navarra, Centro de Investigación Médica Aplicada Project, Red Temática de Investigación Cooperativa de Centros de Cáncer (C03-10), and Red Nacional de Investigación en Hepatología y Gastroenterología (C03-02). S.S.G. is supported by the US National Institutes of Health and the Department of Energy.

¹: I.P. and G.M. contributed equally to this work.

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Rapid communicationPositron Emission Tomography Imaging of Adenoviral-Mediated Transgene Expression in Liver Cancer Patients

Section snippets

Patients and Study Design

Results

Discussion

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Mol Imaging Biol

Mol Imaging Biol

Curr Opin Biotechnol

Mol Imaging Biol

Mol Ther

Lancet

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Nature

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Science

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J Nucl Med

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Nat Rev Cancer

Rapid communication
Positron Emission Tomography Imaging of Adenoviral-Mediated Transgene Expression in Liver Cancer Patients