Endovascular selective intra-arterial infusion of mesenchymal stem cells loaded with Delta-24 in a canine model

Visish M. Srinivasan, Joy Gumin, Kevin M. Camstra, Dalis E. Collins, Melissa M. Chen, Elizabeth J. Shpall, Brittany C. Parker Kerrigan, Jeremiah N. Johnson, Stephen R. Chen, Juan Fueyo, Cande Gomez-Manzano, Frederick F. Lang, Peter Kan

Research output: Contribution to journalArticlepeer-review

Abstract

BACKGROUND: Delta-24-RGD, an oncolytic adenovirus, shows promise against glioblastoma. To enhance virus delivery, we recently demonstrated that human bone marrow-derived mesenchymal stem cells loaded with Delta-24-RGD (hMSC-D24) can eradicate glioblastomas in mouse models. There are no studies examining the safety of endovascular selective intra-arterial (ESIA) infusions of MSC-D24 in large animals simulating human clinical situations. OBJECTIVE: To perform canine preclinical studies testing the feasibility and safety of delivering increasing doses of hMSCs-D24 via ESIA infusions. METHODS: ESIA infusions of hMSC-D24 were performed in the cerebral circulation of 10 normal canines in the target vessels (internal carotid artery [ICA]/P1) via trans-femoral approach using commercially available microcatheters. Increasing concentrations of hMSC-D24 or particles (as a positive control) were injected into 1 hemisphere; saline (negative control) was infused contralaterally. Toxicity (particularly embolic stroke) was assessed on postinfusion angiography, diffusion-weighted magnetic resonance imaging, clinical exam, and necropsy. RESULTS: ESIA injections were performed in the ICA (n = 7) or P1 (n = 3). In 2 animals injected with particles (positive control), strokes were detected by all assays. Of 6 canines injected with hMSC-D24 through the anterior circulation, escalating dose from 2 × 106 cells/20 mL to 1 × 108 cells/10 mL resulted in no strokes. Two animals had ischemic and hemorrhagic strokes after posterior cerebral artery catheterization. A survival experiment of 2 subjects resulted in no complications detected for 24-h before euthanization. CONCLUSION: This novel study simulating ESIA infusion demonstrates that MSCs-D24 can be infused safely at least up to doses of 1 × 108 cells/10 mL (107 cells/ml) in the canine anterior circulation using commercially available microcatheters. These findings support a clinical trial of ESIA infusion of hMSCs-D24.

Original languageEnglish (US)
Pages (from-to)E102-E113
JournalNeurosurgery
Volume88
Issue number1
DOIs
StatePublished - Jan 1 2021

Keywords

  • Cerebrovascular
  • Endovascular
  • Glioblastoma
  • Glioma
  • Intra-arterial
  • Microcatheter
  • Superselective

ASJC Scopus subject areas

  • Surgery
  • Clinical Neurology

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