Endovascular Selective Intra-Arterial Infusion of Mesenchymal Stem Cells Loaded With Delta-24 in a Canine Model

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 transfemoral 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.

Perfusion-guided endovascular super-selective intra-arterial infusion for treatment of malignant brain tumors

“…Prior studies have shown that human bone marrow-derived MSCs can home to gliomas 11 and be successfully loaded with Delta-24 (MSC-D24) for IA delivery. 9 Yttrium-90 microspheres are 25-35 micron glass or resin spheres that can deliver lethal doses of radiation. Each sphere delivers 90% of radiation dose within 5 mm and 11 days.…”

Intraarterial delivery of virotherapy for glioblastoma

“…IA delivery of MSCs loaded with OVs (Delta-24) has been studied in an in vitro endovascular model 35 as well as in a large animal canine model. 36 These experiments have shown that IA microcatheter delivery of MSCs carrying OV retains the oncolytic effects of the virus as well as the tropism of the MSCs. Such delivery is quite robust, unaffected by various catheter factors (positioning/shape, infusion speed, or catheter type).…”

Oncolytic Virus‐Driven Biotherapies from Bench to Bedside

“…demonstrated that hMSCs‐D24 can be infused at safe doses of up to 1 × 10 8 cells/10 mL via endovascular selective intra‐arterial infusion. [ 143 ] These positive results suggest that intra‐arterial delivery is an effective and safe delivery strategy for OVT in patients with stage III OSCC, multifocal HCC, and some intracranial tumors, with promise for clinical translation in the future.…”