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Published on: January 7, 2019
Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy
Matthias Duebgen1, Jordi Martinez-Quintanilla1, Kaoru Tamura1
1Affiliations of authors: Molecular Neurotherapy and Imaging Laboratory (MD, JM-Q, SH, NR, HW, KS), Department of Radiology (MD, JM-Q, KT, SH, NR, HW, KS), Department of Neurosurgery (NR, HW), and Department of Neurology (KS), Massachusetts General Hospital, Harvard Medical School, Boston, MA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA (KS).
Background:
The current treatment regimen for malignant glioblastoma multiforme (GBM) is tumor resection followed by chemotherapy and radiation therapy. Despite the proven safety of oncolytic herpes simplex virus (oHSV) in clinical trials for GBMs, its efficacy is suboptimal mainly because of insufficient viral spread after tumor resection.
Methods:
Human mesenchymal stem cells (MSC) were loaded with oHSV (MSC-oHSV), and their fate was explored by real-time imaging in vitro and in vivo. Using novel diagnostic and armed oHSV mutants and real-time multimodality imaging, the efficacy of MSC-oHSV and its proapoptotic variant, oHSV-TRAIL encapsulated in biocompatible synthetic extracellular matrix (sECM), was tested in different mouse GBM models, which more accurately reflect the current clinical settings of malignant, resistant, and resected tumors. All statistical tests were two-sided.
Results:
MSC-oHSVs effectively produce oHSV progeny, which results in killing of GBMs in vitro and in vivo mediated by a dynamic process of oHSV infection and tumor destruction. sECM-encapsulated MSC-oHSVs result in statistically significant increased anti-GBM efficacy compared with direct injection of purified oHSV in a preclinical model of GBM resection, resulting in prolonged median survival in mice (P < .001 with Gehan-Breslow-Wilcoxin test). To supersede resistant tumors, MSC loaded with oHSV-TRAIL effectively induce apoptosis-mediated killing and prolonged median survival in mice bearing oHSV- and TRAIL-resistant GBM in vitro (P < .001 with χ(2) contingency test).
Conclusions:
Human MSC loaded with different oHSV variants provide a platform to translate oncolytic virus therapies to clinics in a broad spectrum of GBMs after resection and could also have direct implications in different cancer types.
Insights
Human mesenchymal stem cells loaded with oncolytic herpes simplex virus (oHSV) improve glioblastoma multiforme (GBM) treatment efficacy. This novel approach enhances viral spread and tumor destruction, offering a promising platform for oncolytic virotherapy.
Area of Science:
- Oncolytic virotherapy
- Cancer biology
- Stem cell therapy
Background:
- Malignant glioblastoma multiforme (GBM) treatment involves surgery, chemotherapy, and radiation.
- Oncolytic herpes simplex virus (oHSV) is safe for GBM but has suboptimal efficacy due to limited viral spread post-resection.
Purpose of the Study:
- To enhance the efficacy of oncolytic herpes simplex virus (oHSV) for glioblastoma multiforme (GBM) treatment.
- To investigate the use of human mesenchymal stem cells (MSCs) as a delivery vehicle for oHSV.
- To evaluate oHSV variants encapsulated in synthetic extracellular matrix (sECM) for improved anti-GBM activity.
Main Methods:
- Human mesenchymal stem cells (MSCs) were loaded with oHSV (MSC-oHSV) and tracked in vitro and in vivo.
- Novel diagnostic and armed oHSV mutants were used with multimodality imaging.
- The efficacy of MSC-oHSV and oHSV-TRAIL encapsulated in sECM was tested in preclinical mouse GBM models.
Main Results:
- MSC-oHSVs effectively produced oHSV progeny, leading to GBM cell killing in vitro and in vivo.
- sECM-encapsulated MSC-oHSVs demonstrated significantly increased anti-GBM efficacy compared to direct oHSV injection, prolonging median survival.
- MSC loaded with oHSV-TRAIL induced apoptosis-mediated killing in resistant GBM models, significantly prolonging median survival.
Conclusions:
- Human MSCs loaded with oHSV variants offer a viable platform for oncolytic virus therapy in resected GBM.
- This approach has broad applicability for various GBM subtypes and potential implications for other cancer types.
