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

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dc.contributor.authorRossmeisl, John H. Jr.en
dc.contributor.authorHerpai, Deniseen
dc.contributor.authorQuigley, Mindyen
dc.contributor.authorCecere, Thomas E.en
dc.contributor.authorRobertson, John L.en
dc.contributor.authorD'Agostino, Ralph B.en
dc.contributor.authorHinckley, Jonathanen
dc.contributor.authorTatter, Stephen B.en
dc.contributor.authorDickinson, Peter J.en
dc.contributor.authorDebinski, Waldemaren
dc.contributor.departmentSmall Animal Clinical Sciencesen
dc.contributor.departmentBiomedical Sciences and Pathobiologyen
dc.date.accessioned2021-08-02T13:14:52Zen
dc.date.available2021-08-02T13:14:52Zen
dc.date.issued2021-03en
dc.description.abstractBackground. The interleukin-13 receptor alpha 2 (IL13RA2) and ephrin type A receptor 2 (EPHA2) are attractive therapeutic targets, being expressed in similar to 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. Methods. 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. Results. 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 mu g/mL delivered to the target volume (median, 0.099 mu g/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 mu g/mL. Conclusions. This study provides preclinical data fundamental to the translation of this multireceptor targeted therapeutic approach to the human clinic.en
dc.description.notesThis work was supported by grants from the Wake Forest University Translational Sciences Institute, National Cancer Institute (R01CA139099, R01CA74145, P01CA207206), the Comprehensive Cancer Center of Wake Forest University Brain Tumor Center of Excellence, Hearn Fund for Brain Tumor Research, Pratto Fund for Brain Tumor Research, and Dallas Ray Swing Brain Tumor Fund.en
dc.description.sponsorshipWake Forest University Translational Sciences Institute, National Cancer Institute [R01CA139099, R01CA74145, P01CA207206]; Comprehensive Cancer Center of Wake Forest University Brain Tumor Center of Excellence; Hearn Fund for Brain Tumor Research; Pratto Fund for Brain Tumor Research; Dallas Ray Swing Brain Tumor Funden
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1093/neuonc/noaa196en
dc.identifier.eissn1523-5866en
dc.identifier.issn1522-8517en
dc.identifier.issue3en
dc.identifier.pmid32812637en
dc.identifier.urihttp://hdl.handle.net/10919/104472en
dc.identifier.volume23en
dc.language.isoenen
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.subjectanimal modelsen
dc.subjectbacterial cytotoxinsen
dc.subjectcanineen
dc.subjectglioblastomaen
dc.subjectinterstitial drug deliveryen
dc.titlePhase I trial of convection-enhanced delivery of IL13RA2 and EPHA2 receptor targeted cytotoxins in dogs with spontaneous intracranial gliomasen
dc.title.serialNeuro-Oncologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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