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

TY - JOUR

T1 - Preclinical analysis of human mesenchymal stem cells: tumor tropism and therapeutic efficiency of local HSV-TK suicide gene therapy in glioblastoma

AU - Dührsen, Lasse

AU - Hartfuß, Sophie

AU - Hirsch, Daniela

AU - Geiger, Sabine

AU - Maire, Cecile L

AU - Sedlacik, Jan

AU - Guenther, Christine

AU - Westphal, Manfred

AU - Lamszus, Katrin

AU - Hermann, Felix G

AU - Schmidt, Nils Ole

N1 - Copyright: © 2019 Dührsen et al.

PY - 2019/10/22

Y1 - 2019/10/22

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.27071

DO - 10.18632/oncotarget.27071

M3 - SCORING: Journal article

C2 - 31692882

VL - 10

SP - 6049

EP - 6061

JO - ONCOTARGET

JF - ONCOTARGET

SN - 1949-2553

IS - 58

ER -