title: Encapsulated stem cells loaded with hyaluronidase-expressing oncolytic virus for brain tumor therapy.
abstract: Despite the proven safety of oncolytic viruses (OV) in clinical trials for glioblastoma (GBM), their efficacy has been hindered by suboptimal spreading within the tumor. We show that hyaluronan or hyaluronic acid (HA), an important component of extracellular matrix (ECM), is highly expressed in a majority of tumor xenografts established from patient-derived GBM lines that present both invasive and nodular phenotypes. Intratumoral injection of a conditionally replicating adenovirus expressing soluble hyaluronidase (ICOVIR17) into nodular GBM, mediated HA degradation and enhanced viral spread, resulting in a significant antitumor effect and mice survival. In an effort to translate OV-based therapeutics into clinical settings, we encapsulated human adipose-derived mesenchymal stem cells (MSC) loaded with ICOVIR17 in biocompatible synthetic extracellular matrix (sECM) and tested their efficacy in a clinically relevant mouse model of GBM resection. Compared with direct injection of ICOVIR17, sECM-MSC loaded with ICOVIR17 resulted in a significant decrease in tumor regrowth and increased mice survival. This is the first report of its kind revealing the expression of HA in GBM and the role of OV-mediated HA targeting in clinically relevant mouse model of GBM resection and thus has clinical implications.
authors.affiliation: 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Jordi
authors.initials: J
authors.lastname: Martinez-Quintanilla
authors.affiliation: 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Derek
authors.initials: D
authors.lastname: He
authors.affiliation: 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [3] Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.affiliation: Laboratori de Recerca Traslacional IDIBELL-Institut Català d'Oncologia, L'Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Alemany
authors.affiliation: 1] Molecular Neurotherapy and Imaging Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [2] Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [3] Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA [4] Harvard Stem Cell Institute, Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Khalid
authors.initials: K
authors.lastname: Shah
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D045744:Cell Line, Tumor; D005109:Extracellular Matrix / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D005909:Glioblastoma / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D057809:HEK293 Cells; D006801:Humans; D006820:Hyaluronic Acid / Q000378:metabolism; D006821:Hyaluronoglucosaminidase / Q000235:genetics* / Q000378:metabolism; D015552:Injections, Intralesional; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D016019:Survival Analysis; D014764:Viral Proteins / Q000235:genetics* / Q000378:metabolism; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D014764:Viral Proteins; D006820:Hyaluronic Acid; D006821:Hyaluronoglucosaminidase