Oncotarget

Research Papers:

Preclinical analysis of human mesenchymal stem cells: tumor tropism and therapeutic efficiency of local HSV-TK suicide gene therapy in glioblastoma

Lasse Dührsen, Sophie Hartfuß, Daniela Hirsch, Sabine Geiger, Cecile L. Maire, Jan Sedlacik, Christine Guenther, Manfred Westphal, Katrin Lamszus, Felix G. Hermann and Nils Ole Schmidt

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Oncotarget. 2019; 10:6049-6061. https://doi.org/10.18632/oncotarget.27071

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Abstract

Lasse Dührsen1, Sophie Hartfuß1, Daniela Hirsch2, Sabine Geiger2, Cecile L. Maire1, Jan Sedlacik3, Christine Guenther2, Manfred Westphal1, Katrin Lamszus1, Felix G. Hermann2 and Nils Ole Schmidt1

1 Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

2 Apceth Biopharma, 81377 Munich, Germany

3 Department of Neuroradiology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany

Correspondence to:

Nils Ole Schmidt,email: nschmidt@uke.de

Keywords: glioblastoma; brain tumor; stem cells; gene therapy; migration

Received: January 27, 2019     Accepted: June 19, 2019     Published: October 22, 2019

ABSTRACT

Glioblastoma are highly invasive and associated with limited therapeutic options and a grim prognosis. Using stem cells to extend current therapeutic strategies by targeted drug delivery to infiltrated tumors cells is highly attractive. This study analyzes the tumor homing and therapeutic abilities of clinical grade human mesenchymal stem cells (MSCs) in an orthotopic glioblastoma mouse model. Our time course analysis demonstrated that MSCs display a rapid targeted migration to intracerebral U87 glioma xenografts growing in the contralateral hemisphere within the first 48h hours after application as assessed by histology and 7T magnetic resonance imaging. MSCs accumulated predominantly peritumorally but also infiltrated the main tumor mass and targeted distant tumor satellites while no MSCs were found in other regions of the brain. Intratumoral application of MSCs expressing herpes simplex virus thymidine kinase followed by systemic prodrug application of ganciclovir led to a significant tumor growth inhibition of 86% versus the control groups (p<0.05), which translated in a significant prolonged survival time (p<0.05). This study demonstrates that human MSCs generated according to apceth’s GMP process from healthy donors are able to target and provide a significant growth inhibition in a glioblastoma model supporting a potential clinical translation.


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