Positron-emission-tomography monitoring of anti-glioblastoma HSV-1-tk gene therapy

Abstract

A phase I/II clinical trial of gene therapy for recurrent glioblastoma has been initiated in which non-invasive monitoring of the critical steps is performed by a combination of standard clinical positron-emission tomography (PET) for metabolic identification/evaluation of malignant lesions with pioneering PET imaging of HSV-1- tk transgene expression. Localization, characterization and trial follow-up of target tumors rely on multitracer PET brain imaging probed with radiolabeled 2-[ 18 F]fluoro-2-deoxy-D-glucose (FDG), methyl-[ 11 C]-L-methionine (MET) and 3´-deoxy-3´-[ 18 F]fluoro-L-thymidine (FLT) while the location, magnitude and duration of therapeutic HSV-1- tk transgene expression is monitored with 2´-fluoro-2´-deoxy-1-β-D-arabinofuranosyl-5-[ 124 I]iod ([ 124 I]-FIAU). In addition, in order to improve the distribution of the vector within the tumor tissue, a stereotactically guided convection-enhanced delivery (CED) protocol was devised in which the transfection of the HSV-1- tk gene into brain tumor cells is mediated by a liposome-DNA complex. Preliminary findings on a first group of five patients demonstrated that FIAU-PET imaging of HSV-1- tk expression in patients with glioblastoma is feasible and that vector-mediated gene expression may predict the therapeutic effect of ganciclovir prodrug activation. In addition, they showed that integration of magnetic resonance (MR) and PET imaging data into a 3D stereotaxic coordinate system results in an efficient non-invasive spatio-temporal monitoring of a brain gene therapy trial. Such a non-invasive imaging provides the means to identify potential critical parameters and to implement dosing/ routing adjustments that will have a critical impact on the development of standardized gene therapy protocols.