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

Abstract

Background The interleukin 13 receptor alpha 2 (IL13RA2) and ephrin type-A receptor 2 (EPHA2) receptors 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. 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 end point 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 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. Conclusions This study provides pre-clinical data fundamental to the translation of this multi-receptor targeted therapeutic approach to the human clinic.

Clinical features, diagnosis, and survival analysis of dogs with glioma

“… 59 , 60 , 61 , 62 , 63 Case series with palliative treatment outcome information relating to glioma type or grade are lacking. Canine studies evaluating experimental therapies in >3 intracranial gliomas with detailed information on their type and grade have reported MSTs of 119 days (n = 7), 64 224 days (n = 17), 65 248 days (n = 8), 66 and 257 days (n = 8). 67 However, no comparisons were made between differing types or grades.…”

Non-Invasive Low Pulsed Electrical Fields for Inducing BBB Disruption in Mice—Feasibility Demonstration

“…Research for CNS drug delivery focuses on three main approaches [ 3 ]: (1) reformulating existing drugs to cross the BBB by physiological transport mechanisms and drug-delivery approaches such as microspheres and colloidal drug-carriers [ 4 ]; (2) minimally invasive/invasive local delivery methods such as convection-enhanced delivery [ 5 , 6 ] and biodegradable wafers; and (3) disrupting the BBB, where non-localized methods include osmotic BBB disruption (BBBd) [ 7 ], while localized approaches include laser interstitial thermotherapy, MRI-guided focused ultrasound (MRgFUS) [ 8 ] and electroporation (EP) [ 9 ].…”

Radiotherapy of High-Grade Gliomas: First Half of 2021 Update with Special Reference to Radiosensitization Studies

“…However, radiosensitizing drugs may not easily cross the blood-brain barrier and may possibly exert toxic effects per se when administered systemically. On the other hand, locoregional administration of radiosensitizing drugs (e.g., through convection-enhanced delivery) is of difficult technical implementation and at the moment can be performed in few clinical centers only [104,105]. Inhibiting minimal residual disease progression using low doses of radiation delivered soon after guideline therapies may be an alternative fruitful strategy: in multiple glioma initiating cell-driven animal models that accurately recapitulate the heterogeneity and growth patterns of the patients' tumors, it was recently demonstrated that ultra-hyper-FRT started at early stages of tumor progression resulted in a significant delay in tumor progression and an improvement in animal survival [55].…”