1. ¹Abteilung für Neuropathologie, Universität zu Köln, Köln, Germany
2. ²Georg-Speyer-Haus, Frankfurt am Main, Germany
3. ³Neural Regeneration Unit, Institute of Reconstructive Neurobiology, University Bonn LIFE & BRAIN Center and Hertie, Foundation, Bonn, Germany
4. ⁴Labor für Gentherapie und Molekulares Imaging, Max-Planck-Institut für Neurologische Forschung, Universität zu Köln, Köln, Germany
5. ⁵In-vivo NMR Laboratory, Max-Planck-Institute for Neurological Research with Klaus-Joachim-Zülch-Laboratories of the Max Planck Society and the Faculty of Medicine of the University of Cologne, Köln, Germany
6. ⁶Bone Marrow Transplant Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Correspondence: Hrvoje Miletic, Abteilung für Neuropathologie, Universität zu Köln, Joseph-Stelzmann-Strasse 9, D-50931 Köln, Germany. E-mail: h.miletic@uni-koeln.de

^*These authors contributed equally to this work.

Received 18 September 2006; Accepted 23 February 2007; Published online 24 April 2007.

Abstract

Adult stem cells are promising cellular vehicles for therapy of malignant gliomas as they have the ability to migrate into these tumors and even track infiltrating tumor cells. However, their clinical use is limited by a low passaging capacity that impedes large-scale production. In the present study, a bone marrow–derived, highly proliferative subpopulation of mesenchymal stem cells (MSCs)—here termed bone marrow–derived tumor-infiltrating cells (BM-TICs)—was genetically modified for the treatment of malignant glioma. Upon injection into the tumor or the vicinity of the tumor, BM-TICs infiltrated solid parts as well as the border of rat 9L glioma. After intra-tumoral injection, BM-TICs expressing the thymidine kinase of herpes simplex virus (HSV-tk) and enhanced green fluorescent protein (BM-TIC-tk-GFP) were detected by non-invasive positron emission tomography (PET) using the tracer 9-[4-[¹⁸F]fluoro-3-hydroxymethyl)butyl]guanine ([¹⁸F]FHBG). A therapeutic effect was demonstrated in vitro and in vivo by BM-TICs expressing HSV-tk through bystander-mediated glioma cell killing. Therapeutic efficacy was monitored by PET as well as by magnetic resonance imaging (MRI) and strongly correlated with histological analysis. In conclusion, BM-TICs expressing a suicide gene were highly effective in the treatment of malignant glioma in a rat model and therefore hold great potential for the therapy of malignant brain tumors in humans.