Real-time, Image-Guided, Convection-Enhanced Delivery of Interleukin 13 Bound to Pseudomonas Exotoxin

Abstract

Purpose: To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin). Experimental Design: Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 Ag/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 Ag/mL; n = 8), co-infusion of 125 I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 Ag/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment. Results: Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 Ag/mL but showed clinical and histologic toxicity at 10 Ag/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution. Conclusions: IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging.

The effects of temozolomide delivered by prolonged intracerebral microinfusion against the rat brainstem GBM allograft model

“…Recently, a rat model of brainstem glioma has been developed [14,30]. Moreover, several feasibility studies were performed with continuous drug infusion into brainstem using carboplatin, BCNU, IL-13-PE, and gemcitabine [5,18,20,24]. Moreover, a beneficial effect of intracerebral (i.c.)…”

Analysis of Biodistribution of Intracranially Infused Radiolabeled Interleukin-13 Receptor–Targeted Immunotoxin IL-13PE by SPECT/CT in an Orthotopic Mouse Model of Human Glioma

“…Previously, 123 I-albumin and gadolinium-albumin tracers have been used to assess drug distribution by CED when coadministered with IL-13PE (9,16). But, this approach may not be comparable from the actual distribution of IL-13PE because of differences in their molecular weights (albumin, 67 kDa vs. IL-13PE, 52 kDa) and binding kinetics.…”

“…In preclinical animal studies, IL-13PE distribution in the brain stem of nonhuman primates was tracked by coinfusion of gadolinium-bound albumin, followed by MR imaging and autoradiography of 125 I-IL-13PE (9). This study did not evaluate binding and cytotoxic activity of the radiolabeled IL-13PE.…”

Convection-enhanced delivery to the central nervous system

“…2,44,49,71 These neurological changes have been attributed to prolonged edema or effects of the drug on tumor (in tumor-specific trials and/or the putative therapeutic infused at doses in a potentially tissue toxic range). Lasting or irreversible neurological changes directly attributed to the convective infusion of substances in the CNS have not occurred over a range of infusate rates, including rates up to 10 ml/min.…”