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

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.

SUBMITTER: Duhrsen L

PROVIDER: S-EPMC6817450 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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

Dührsen Lasse L Hartfuß Sophie S Hirsch Daniela D Geiger Sabine S Maire Cecile L CL Sedlacik Jan J Guenther Christine C Westphal Manfred M Lamszus Katrin K Hermann Felix G FG Schmidt Nils Ole NO

Oncotarget 20191022 58

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 ...[more]

PMID: 31692882

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Project description:BackgroundGlioblastoma (GBM) is the most frequent and aggressive brain tumor in adults with the lowest survival rates five years post-diagnosis. Oncolytic viruses (OVs) selectively target and damage cancer cells, and for this reason they are being investigated as new therapeutic tools also against GBM.MethodsAn oncolytic herpes simplex virus type 1 (oHSV-1) with deletions in the γ34.5 neurovirulence gene and the US12 gene, expressing enhanced green fluorescent protein (EGFP-oHSV-1) as reporter gene was generated and tested for its capacity to infect and kill the murine GL261 glioblastoma (GBM) cell line. Syngeneic mice were orthotopically injected with GL261cells. Seven days post-implantation, EGFP-oHSV-1 was administered intratumorally. Twenty-one days after parental tumor challenge in the opposite brain hemisphere, mice were sacrified and their brains were analysed by immunohistochemistry to assess tumor presence and cell infiltrate.ResultsoHSV-1 replicates and induces cell death of GL261 cells in vitro. A single intracranial injection of EGFP-oHSV-1 in established GL261 tumors significantly prolongs survival in all treated mice compared to placebo treatment. Notably, 45% of treated mice became long-term survivors, and rejected GL261 cells upon rechallenge in the contralateral brain hemisphere, indicating an anamnestic antitumoral immune response. Post-mortem analysis revealed a profound modification of the tumor microenvironment with increased infiltration of CD4 + and CD8 + T lymphocytes, intertumoral vascular collapse and activation and redistribution of macrophage, microglia, and astroglia in the tumor area, with the formation of intense fibrotic tissue suggestive of complete rejection in long-term survivor mice.ConclusionsEGFP-oHSV1 demonstrates potent antitumoral activity in an immunocompetent GBM model as a monotherapy, resulting from direct cell killing combined with the stimulation of a protective adaptive immune response. These results open the way to possible application of our strategy in clinical setting.

Dataset Information

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

Publications

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

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