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Phase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomas.

Authors
  • Rossmeisl, John H1, 2, 3, 4
  • Herpai, Denise1
  • Quigley, Mindy3
  • Cecere, Thomas E5
  • Robertson, John L1, 2, 4
  • D'Agostino, Ralph B1, 6
  • Hinckley, Jonathan1
  • Tatter, Stephen B1, 7
  • Dickinson, Peter J8
  • Debinski, Waldemar1, 4, 9
  • 1 Comprehensive Cancer Center and Brain Tumor Center of Excellence of Wake Forest University, Winston-Salem, North Carolina.
  • 2 Veterinary and Comparative Neurooncology Laboratory, Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia.
  • 3 Department of Small Animal Clinical Sciences, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia.
  • 4 Virginia Tech-Wake Forest University School of Biomedical Engineering and Sciences, Blacksburg, Virginia.
  • 5 Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, Virginia.
  • 6 Department of Biostatistics and Data Science, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • 7 Department of Neurosurgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina.
  • 8 Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, California (P.J.D.).
  • 9 Department of Cancer Biology of Wake Forest University, Winston-Salem, North Carolina.
Type
Published Article
Journal
Neuro-Oncology
Publisher
Oxford University Press
Publication Date
Mar 25, 2021
Volume
23
Issue
3
Pages
422–434
Identifiers
DOI: 10.1093/neuonc/noaa196
PMID: 32812637
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The interleukin-13 receptor alpha 2 (IL13RA2) and ephrin type A receptor 2 (EPHA2) are attractive therapeutic targets, being expressed in ~90% of canine and human gliomas, and absent in normal brain. Clinical trials using an earlier generation IL-13 based cytotoxin showed encouraging clinical effects in human glioma, but met with technical barriers associated with the convection-enhanced delivery (CED) method. In this study, IL-13 mutant and ephrin A1 (EFNA1)-based bacterial cytotoxins targeted to IL13RA2 and EPHA2 receptors, respectively, were administered locoregionally by CED to dogs with intracranial gliomas to evaluate their safety and preliminary efficacy. In this phase I, 3 + 3 dose escalation trial, cytotoxins were infused by CED in 17 dogs with gliomas expressing IL13RA2 or EPHA2 receptors. CED was performed using a shape-fitting therapeutic planning algorithm, reflux-preventing catheters, and real-time intraoperative MRI monitoring. The primary endpoint was to determine the maximum tolerated dose of the cytotoxic cocktail in dogs with gliomas. Consistent intratumoral delivery of the cytotoxic cocktail was achieved, with a median target coverage of 70% (range, 40-94%). Cytotoxins were well tolerated over a dose range of 0.012-1.278 μg/mL delivered to the target volume (median, 0.099 μg/mL), with no dose limiting toxicities observed. Objective tumor responses, up to 94% tumor volume reduction, were observed in 50% (8/16) of dogs, including at least one dog in each dosing cohort >0.05 μg/mL. This study provides preclinical data fundamental to the translation of this multireceptor targeted therapeutic approach to the human clinic. © The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

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