Interstitial Infusion of IL13-PE38QQR in the Rat Brain Stem

Souweidane, Mark M.; Occhiogrosso, G.; Mark, Erika B.; Edgar, Mark A.

doi:10.1023/b:neon.0000024219.47447.91

Cited by 28 publications

(15 citation statements)

References 36 publications

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“…16,32 Consistent with a previous report of IL13-PE infusion in a child with a DIPG, 18 the Vd:Vi ratio in our patients was significantly lower (range 1.6–4.1). Notwithstanding the reduction in Vd:Vi ratio due to coinfusion with a lower concentration of Gd-DTPA (Case 1; Gd-DTPA infusion concentration of 1 mM), the reduced efficiency in distribution in these case is likely the result of expansion of the extracellular space due to vasogenic edema.…”

Section: Discussionsupporting

confidence: 92%

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas

Chittiboina

Heiss

Warren

et al. 2014

PED

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Object Coinfused surrogate imaging tracers can provide direct insight into the properties of convection-enhanced delivery (CED) in the nervous system. To better understand the distributive properties of CED in a clinical circumstance, the authors analyzed the imaging findings in pediatric diffuse intrinsic pontine glioma (DIPG) patients undergoing coinfusion of Gd-DTPA and interleukin-13–Pseudomonas exotoxin (IL13-PE). Methods Consecutive patients undergoing CED (maximal rates of 5 or 10 μl/minute) of Gd-DTPA (1 or 5 mM) and IL13-PE (0.125 μg/ml or 0.25 μg/ml) for DIPG were included. Real-time MRI was performed during infusions, and imaging results were analyzed. Results Four patients (2 males, 2 females; mean age at initial infusion 13.0 ± 5.3 years; range 5–17 years) underwent 5 infusions into DIPGs. Brainstem infusions were clearly identified on T1-weighted MR images at 1-mM (1 infusion) and 5-mM (4 infusions) coinfused Gd-DTPA concentrations. While the volume of distribution (Vd) increased progressively with volume of infusion (Vi) (mean volume 2.5 ± 0.9 ml; range 1.1–3.7 ml), final Vd:Vi ratios were significantly reduced with lower Gd-DTPA concentration (Vd:Vi for 1 mM of 1.6 compared with a mean Vd:Vi ratio for 5 mM of 3.3 ± 1.0) (p = 0.04). Similarly, anatomical distribution patterns were affected by preferential flow along parallel axial fiber tracts, into prior infusion cannula tracts and intraparenchymal air pockets, and leak back around the infusion cannula at the highest rate of infusion. Conclusions Magnetic resonance imaging of a coinfused Gd-DTPA surrogate tracer provided direct insight into the properties of CED in a clinical application. While clinically relevant Vds can be achieved by convective delivery, specific tissue properties can affect distribution volume and pattern, including Gd-DTPA concentration, preferential flow patterns, and infusion rate. Understanding of these properties of CED can enhance its clinical application. Part of clinical trial no. NCT00880061 (ClinicalTrials.gov).

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Section: Discussionsupporting

confidence: 92%

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas

Chittiboina

Heiss

Warren

et al. 2014

PED

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“…Clinical and histologic data confirmed that CED of concentrations up to and including 10 Ag/mL of IL13-PE were well tolerated in the rat brainstem over short-term (3 days postinfusion) and long-term (28 days postinfusion) evaluations. These findings are consistent with previous short-term (<14 days) rat toxicity studies that have shown lack of toxicity with perfusion of the brainstem (48) or the striatum with IL13-PE concentrations of up to 100 Ag/mL (49,50). The delayed evidence of toxicity at the highest concentration infused of IL13-PE (10 Ag/mL) in the primate indicates that IL13-PE toxicity is likely related to nonspecific, concentration-dependent immunotoxin effects on perfused tissue and is not related to CED per se or to the total infused volume of IL13-PE.…”

Section: Current Studysupporting

confidence: 91%

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

Murad

Walbridge

Morrison

et al. 2006

Clinical Cancer Research

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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.

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“…Thomale et al 108 reported on the safe placement of up to 3 cannulas in the brainstems of rats for local drug delivery, and the drug distribution was greater in the 3-cannula group than in the 1-cannula group. Because CED can be used for the delivery of large macromolecules, such as targeted toxins or monoclonal antibodies, Souweidane et al 102 showed that the tumor-specific chimeric cytotoxin IL13-PE38QQR can be safely delivered into the rat brainstem via interstitial infusion. This recombinant cytotoxin is a combination of the cytokine interleukin-13 and the modified Pseudomonas exotoxin moiety PE A , and this chimeric cytotoxin has been shown to be highly selective for glioma cells, with proven cytotoxicity in experimental studies.…”

Section: New Therapeutic Perspective Strategiesmentioning

confidence: 99%

Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies

Frazier¹,

Lee²,

Thomale

et al. 2009

PED

125

107

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Diffuse intrinsic pontine gliomas constitute ~ 60–75% of tumors found within the pediatric brainstem. These malignant lesions present with rapidly progressive symptoms such as cranial nerve, long tract, or cerebellar dysfunctions. Magnetic resonance imaging is usually sufficient to establish the diagnosis and obviates the need for surgical biopsy in most cases. The prognosis of the disease is dismal, and the median survival is < 12 months. Resection is not a viable option. Standard therapy involves radiotherapy, which produces transient neurological improvement with a progression-free survival benefit, but provides no improvement in overall survival. Clinical trials have been conducted to assess the efficacy of chemotherapeutic and biological agents in the treatment of diffuse pontine gliomas. In this review, the authors discuss recent studies in which systemic therapy was administered prior to, concomitantly with, or after radiotherapy. For future perspective, the discussion includes a rationale for stereotactic biopsies as well as possible therapeutic options of local chemotherapy in these lesions.

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Interstitial Infusion of IL13-PE38QQR in the Rat Brain Stem

Cited by 28 publications

References 36 publications

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas

Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas

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

Treatment of diffuse intrinsic brainstem gliomas: failed approaches and future strategies

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