title: A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma.
abstract: Glioblastoma multiforme is a primary malignancy of the central nervous system that is universally fatal due to its disseminated nature. Recent investigations have focused on the unique tumor-tropic properties of stem cells as a novel platform for targeted delivery of anticancer agents to the brain. Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) both have the potential to function as cell carriers for targeted delivery of a glioma restricted oncolytic virus to disseminated tumor due to their reported tumor tropism. In this study, we evaluated NSCs and MSCs as cellular delivery vehicles for an oncolytic adenovirus in the context of human glioma. We report the first preclinical comparison of the two cell lines and show that, while both stem cell lines are able to support therapeutic adenoviral replication intracellularly, the amount of virus released from NSCs was a log higher than the MSC (p < 0.001). Moreover, only virus loaded NSCs that were administered intracranially in an orthotopic glioma model significantly prolonged the survival of tumor bearing animals (median survival for NSCs 68.5 days vs 44 days for MSCs, p < 0.002). Loading oncolytic adenovirus into NSCs and MSCs also led to expression of both pro- and anti-inflammatory genes and decreased vector-mediated neuroinflammation. Our results indicate that, despite possessing a comparable migratory capacity, NSCs display superior therapeutic efficacy in the context of intracranial tumors. Taken together, these findings argue in favor of NSCs as an effective cell carrier for antiglioma oncolytic virotherapy.
authors: The Brain Tumor Center, The University of Chicago, Chicago, Illinois 60637, USA.
authors: Atique U
authors: AU
authors: Ahmed
authors: Matthew A
authors: MA
authors: Tyler
authors: Bart
authors: B
authors: Thaci
authors: Nikita G
authors: NG
authors: Alexiades
authors: Yu
authors: Y
authors: Han
authors: Ilya V
authors: IV
authors: Ulasov
authors: Maciej S
authors: MS
authors: Lesniak
mesh_terms: D000256:Adenoviridae / Q000472:pathogenicity / Q000502:physiology*; D000257:Adenoviridae Infections / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D000818:Animals; D001932:Brain Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D018792:Encephalitis, Viral / Q000276:immunology / Q000503:physiopathology / Q000821:virology; D005910:Glioma / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods; D059630:Mesenchymal Stem Cells / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D058953:Neural Stem Cells / Q000637:transplantation* / Q000821:virology; D050130:Oncolytic Virotherapy / Q000009:adverse effects / Q000379:methods*; D050504:Oncolytic Viruses / Q000472:pathogenicity / Q000502:physiology*; D011897:Random Allocation; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D057074:Virus Release; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays