Convection-enhanced delivery of free gadolinium with the recombinant immunotoxin MR1-1

Abstract

Purpose A major obstacle in glioblastoma (GBM) therapy is the restrictive nature of the blood-brain barrier (BBB). Convection-enhanced delivery (CED) is a novel method of drug administration which allows direct parenchymal infusion of therapeutics, bypassing the BBB. MR1-1 is a novel recombinant immunotoxin that targets the GBM tumor-specific antigen EGFRvIII and can be delivered via CED infusion. However, drug distribution via CED varies dramatically, which necessitates active monitoring. Gadolinium conjugated to diethylenetriamine penta-acetic acid (Gd-DTPA) is a commonly used MRI contrast agent which can be co-infused with therapies using CED and may be useful in monitoring infusion leak and early distribution. Experimental design Forty immunocompetent rats were implanted with intracerebral cannulas that were connected to osmotic pumps and subsequently randomized into four groups that each received 0.2% human serum albumin (HSA) mixed with a different experimental infusion: 1) 25 ng/mL MR1-1; 2) 7 μmol/mL Gd-DTPA; 3) 25 ng/mL MR1-1 and 7 μmol/mL Gd-DTPA; 4) 250 ng/mL MR1-1 and 7μmol/mL Gd-DTPA. The rats were monitored clinically for six weeks then necropsied and histologically assessed for CNS toxicity. Results All rats survived the entirety of the study without clinical or histological toxicity attributable to the study drugs. There was no statistically significant difference in weight change over time among groups (p>0.999). Conclusion MR1-1 co-infused with Gd-DTPA via CED is safe in the long-term setting in a pre-clinical animal model. Our data supports the use of Gd-DTPA, as a surrogate tracer, co-infused with MR1-1 for drug distribution monitoring in patients with GBM.

Efficacy of vincristine administered via convection-enhanced delivery in a rodent brainstem tumor model documented by bioluminescence imaging

“…It is a promising delivery method for large therapeutic agents such as monoclonal antibodies [36], antisense oligonucleotides [37], immunotoxins [38,39], or viral vectors [40,41]. It may prove beneficial in combination with radiotherapy for the treatment of brain tumors [42], and it can be combined with MRI to monitor drug delivery [43,44]. CED allows for the treatment of tumors in large brain regions, such as the brain stem, frontal lobe, temporal lobe, etc., and allows for delivery of agents that may not cross the BBB or are too toxic if delivered systemically.…”

Convection-enhanced delivery to the central nervous system

“…3). 3,16,22,25,27,29,59,76,106 Because CED relies on bulk flow and because most large-and many small-molecular-weight compounds distribute at a similar rate during the typical time course of CED, surrogate tracers that differ substantially in size from the putative therapeutic can often be used to track drug distribution over infusion volumes necessary to treat many neurological disorders.…”

Current status of intratumoral therapy for glioblastoma

“…If CED is applied after resection of a brain tumor, the microinfusion catheters placed under stereotactic guidance target the peritumoral region with bulk flow, supplementing intrinsic diffusivity of either small or large therapeutic compounds to greatly enhance their distribution within the brain [21]. Since CED depends on fluid flow to carry the agent, it is possible to achieve a relatively constant concentration of drug spanning a predictable distance from the infusion site before the drop-off [23]. This provides superior localization to residual tumor cells, given accurate catheter placement [23,24].…”