Endovascular Superselective Intra-arterial infusion of Mesenchymal Stem Cells loaded with Delta-24 in a Canine Model
Visish Srinivasan, Peter Kan, Frederick Lang, Elizabeth Shpall
Introduction: Delta-24-RGD, an oncolytic adenovirus showing promise in clinical trials against glioblastoma. In an effort to enhance delivery of this virus, we recently demonstrated that human Mesenchymal Stem Cells loaded with Delta-24-RGD (hMSC-D24) are capable of eradicating glioblastoms in mouse models. However, there are no studies examining the safety of modern endovascular super-selective intra-arterial (ESSIA) injections of MSC-D24 in animals large enough to simulate human situations.
Objective: Therefore, we undertook preclinical studies in canines to test the feasibility of delivering increasing doses of MSCs-D24 via ESSIA injections.
Methods: The cerebral circulation was accessed via a transfemoral approach, and ESSIA infusions of GMP-grade hMSC-D24 were performed in the target vessels (ICA or P1) using clinical-grade microcatheters. Increasing concentrations of hMSC-D24 or particles (as a positive control) were injected into one hemisphere, and saline (negative control) was injected into the opposite hemisphere. Toxicity (stroke) was assessed by post-infusion angiography, MRI, and necropsy.
Results: ESSIA injections were performed in 10 canines (anterior circulation, N=7; posterior circulation, N=3). In two positive controls, strokes were detected by all assays. Of 8 canines injected with hMSC-D24, escalating from 2x10^6 cells/20mL to 1x10^8 cells/10mL resulted in no strokes. In comparison, 1 (12%) of 8 hemispheres infused with saline had stroke. Two subjects were recovered and survived without morbidity for 24-hrs before being euthanized.
Conclusions: This first-of-its-kind study simulating ESSIA infusion of MSCs-D24 demonstrates that hMSC-D24 can be infused safely at least up to doses of 1x10^8 cells/10mL. These findings support a clinical trial of ESSIA infusion of Delta-24-MSCs.