title: Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma.
abstract: Gene therapy represents a promising treatment alternative for patients with malignant gliomas. Nevertheless, in the setting of these highly infiltrative tumors, transgene delivery remains a challenge. Indeed, viral vehicles tested in clinical trials often target only those tumor cells that are adjacent to the injection site. In this study, we examined the feasibility of using human mesenchymal stem cells (hMSC) to deliver a replication-competent oncolytic adenovirus (CRAd) in a model of intracranial malignant glioma. To do so, CRAds with a chimeric 5/3 fiber or RGD backbone with or without CXCR4 promoter driving E1A were examined with respect to replication and toxicity in hMSC, human astrocytes, and the human glioma cell line U87MG by quantitative polymerase chain reaction and membrane integrity assay. CRAd delivery by virus-loaded hMSC was then evaluated in vitro and in an in vivo model of mice bearing intracranial U87MG xenografts. Our results show that hMSC are effectively infected by CRAds that use the CXCR4 promoter. CRAd-CXCR4-RGD had the highest replication, followed by CRAd-CXCR4-5/3, in hMSC, with comparable levels of toxicity. In U87MG tumor cells, CRAd-CXCR4-5/3 showed the highest replication and toxicity. Virus-loaded hMSC effectively migrated in vitro and released CRAds that infected U87MG glioma cells. When injected away from the tumor site in vivo, hMSC migrated to the tumor and delivered 46-fold more viral copies than injection of CRAd-CXCR4-5/3 alone. Taken together, these results indicate that hMSC migrate and deliver CRAd to distant glioma cells. This delivery strategy should be explored further, as it could improve the outcome of oncolytic virotherapy for glioma.
authors.affiliation: Brain Tumor Center, University of Chicago, Chicago, Illinois, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Sonabend
authors.forename: Ilya V
authors.initials: IV
authors.lastname: Ulasov
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Tyler
authors.forename: Angel A
authors.initials: AA
authors.lastname: Rivera
authors.forename: James M
authors.initials: JM
authors.lastname: Mathis
authors.forename: Maciej S
authors.initials: MS
authors.lastname: Lesniak
mesh_terms: D000256:Adenoviridae / Q000502:physiology*; D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement; D005786:Gene Expression Regulation; D005910:Glioma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D051379:Mice; D009368:Neoplasm Transplantation; D050130:Oncolytic Virotherapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic; D014779:Virus Replication
chemical_list: D019718:Receptors, CXCR4