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

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