Stem cells loaded with multimechanistic oncolytic herpes simplex virus variants for brain tumor therapy.
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.
Affiliations 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).
Matthias
M
Duebgen
Affiliations 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).
Jordi
J
Martinez-Quintanilla
Affiliations 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).
Kaoru
K
Tamura
Affiliations 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).
Shawn
S
Hingtgen
Affiliations 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).
Navid
N
Redjal
Affiliations 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).
Hiroaki
H
Wakimoto
Affiliations 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). kshah@mgh.harvard.edu.
Khalid
K
Shah
D000818:Animals; D001932:Brain Neoplasms / Q000628:therapy*; D005260:Female; D005909:Glioblastoma / Q000628:therapy*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000821:virology*; D051379:Mice; D016513:Mice, SCID; D050130:Oncolytic Virotherapy / Q000379:methods*; D018139:Simplexvirus; D023041:Xenograft Model Antitumor Assays