Phase I trial of convection-enhanced delivery of IL13-Pseudomonas toxin in children with diffuse intrinsic pontine glioma

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In Brief

This article reports the results of a Phase I single-institution, open-label, dose-escalation, safety and tolerability study of IL13-PE38QQR infused via convection-enhanced delivery into tumors in 5 pediatric patients with diffuse intrinsic pontine glioma. Clinical safety, imaging, and outcome methods from this trial could be used in future clinical trials.

ABBREVIATIONS CED = convection-enhanced delivery; DIPG = diffuse intrinsic pontine glioma; IL-13 = interleukin 13; IL13R = IL-13 receptor; IPI = Impact of Pediatric Illness; KPS = Karnofsky Performance Status; LPS = Lansky Performance Status; MRS = MR spectroscopy; NAA = n-acetyl aspartate; QOL = quality of life; Vd = volume of distribution; Vi = volume of infusion.

Article Information

Correspondence John D. Heiss: National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD. heissj@ninds.nih.gov.

INCLUDE WHEN CITING Published online December 7, 2018; DOI: 10.3171/2018.9.PEDS17225.

Disclosures The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

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    Second infusion in patient 5. Intraoperative coronal (A) and sagittal-oblique (B) T1-weighted MR images demonstrating retrograde flow of infusate back into the old cannula tract from the infusion 4 weeks prior.

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    Patient 3. Sagittal contrast-enhanced T1-weighted MR images obtained preoperatively (A) and 1 month (B) and 2 (C) and 3 (D) months postoperatively. The 1-month follow-up image (B) shows minimal enhancement, low perfusion, and necrosis at the infusion site consistent with treatment response.

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    Patient 5. Sagittal contrast-enhanced T1-weighted MR images obtained preoperatively (A) and 1 month (B) and 2 (C) and 3 (D) months postoperatively. The 1-month follow-up image (B) shows minimal enhancement, low perfusion, and necrosis at the infusion site consistent with treatment response.

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    Patient 5. MRS findings. A: Before initial infusion: NAA/creatine (Cr) ratio of 0.60, choline (Cho)/Cr ratio of 4.47, and Cho/NAA ratio of 7.44. B: One month postoperatively: NAA/Cr ratio of 10.4, Cho/Cr ratio of 38.3, and Cho/NAA ratio of 3.68. C: Three months postoperatively: NAA/Cr ratio of 0.31, Cho/Cr ratio of 2.76, and Cho/NAA ratio of 8.93.

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    Patient 2. Intraparenchymal air effects on infusate distribution. A–F: Serial axial T1-weighted MR images obtained every 50 minutes, demonstrating the impact of an intraparenchymal air bubble (hypointensity) introduced at the start of the infusion. While there was a small decrease in the volume of air over time, the serial images demonstrate the restriction of anteromedial spread of infusate (hyperintensity) by the air in the parenchyma.

References

1

Albright ALPacker RJZimmerman RRorke LBBoyett JHammond GD: Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brain stem gliomas: a report from the Children’s Cancer Group. Neurosurgery 33:102610301993

2

Broniscer AGajjar A: Supratentorial high-grade astrocytoma and diffuse brainstem glioma: two challenges for the pediatric oncologist. Oncologist 9:1972062004

3

Chittiboina PHeiss JDWarren KELonser RR: Magnetic resonance imaging properties of convective delivery in diffuse intrinsic pontine gliomas. J Neurosurg Pediatr 13:2762822014

4

Debinski WGibo DMHulet SWConnor JRGillespie GY: Receptor for interleukin 13 is a marker and therapeutic target for human high-grade gliomas. Clin Cancer Res 5:9859901999

5

Debinski WObiri NIPastan IPuri RK: A novel chimeric protein composed of interleukin 13 and Pseudomonas exotoxin is highly cytotoxic to human carcinoma cells expressing receptors for interleukin 13 and interleukin 4. J Biol Chem 270:16775167801995

6

Debinski WObiri NIPowers SKPastan IPuri RK: Human glioma cells overexpress receptors for interleukin 13 and are extremely sensitive to a novel chimeric protein composed of interleukin 13 and pseudomonas exotoxin. Clin Cancer Res 1:125312581995

7

García-Fiñana MCruz-Orive LMMackay CEPakkenberg BRoberts N: Comparison of MR imaging against physical sectioning to estimate the volume of human cerebral compartments. Neuroimage 18:5055162003

8

Gholamin SMitra SSFeroze AHLiu JKahn SAZhang M: Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors. Sci Transl Med 9:eaaf29682017

9

Gujar SKMaheshwari SBjörkman-Burtscher ISundgren PC: Magnetic resonance spectroscopy. J Neuroophthalmol 25:2172262005

10

Halvorson KGBarton KLSchroeder KMisuraca KLHoeman CChung A: A high-throughput in vitro drug screen in a genetically engineered mouse model of diffuse intrinsic pontine glioma identifies BMS-754807 as a promising therapeutic agent. PLoS One 10:e01189262015

11

Hargrave DChuang NBouffet E: Conventional MRI cannot predict survival in childhood diffuse intrinsic pontine glioma. J Neurooncol 86:3133192008

12

Howe FABarton SJCudlip SAStubbs MSaunders DEMurphy M: Metabolic profiles of human brain tumors using quantitative in vivo 1H magnetic resonance spectroscopy. Magn Reson Med 49:2232322003

13

Husain SRJoshi BHPuri RK: Interleukin-13 receptor as a unique target for anti-glioblastoma therapy. Int J Cancer 92:1681752001

14

Joshi BHPuri RALeland PVarricchio FGupta GKocak M: Identification of interleukin-13 receptor α2 chain overexpression in situ in high-grade diffusely infiltrative pediatric brainstem glioma. Neuro Oncol 10:2652742008

15

Kawakami MKawakami KPuri RK: Interleukin-4-Pseudomonas exotoxin chimeric fusion protein for malignant glioma therapy. J Neurooncol 65:15252003

16

Kinoshita YYokota A: Absolute concentrations of metabolites in human brain tumors using in vitro proton magnetic resonance spectroscopy. NMR Biomed 10:2121997

17

Kioi MHusain SRCroteau DKunwar SPuri RK: Convection-enhanced delivery of interleukin-13 receptor-directed cytotoxin for malignant glioma therapy. Technol Cancer Res Treat 5:2392502006

18

Kunwar S: Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies. Acta Neurochir Suppl 88:1051112003

19

Kunwar SChang SPrados MBerger MSSampson JHCroteau D: Safety of intraparenchymal convection-enhanced delivery of cintredekin besudotox in early-phase studies. Neurosurg Focus 20(4):E152006

20

Kunwar SChang SWestphal MVogelbaum MSampson JBarnett G: Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol 12:8718812010

21

Kunwar SPrados MDChang SMBerger MSLang FFPiepmeier JM: Direct intracerebral delivery of cintredekin besudotox (IL13-PE38QQR) in recurrent malignant glioma: a report by the Cintredekin Besudotox Intraparenchymal Study Group. J Clin Oncol 25:8378442007

22

Laprie APirzkall AHaas-Kogan DACha SBanerjee ALe TP: Longitudinal multivoxel MR spectroscopy study of pediatric diffuse brainstem gliomas treated with radiotherapy. Int J Radiat Oncol Biol Phys 62:20312005

23

Lonser RRWalbridge SGarmestani KButman JAWalters HAVortmeyer AO: Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg 97:9059132002

24

Lonser RRWarren KEButman JAQuezado ZRobison RAWalbridge S: Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 107:1901972007

25

Office of Human Research Protections: Special protections for children as research subjects. HHS.gov. March 18 2016 (https://www.hhs.gov/ohrp/regulations-and-policy/guidance/special-protections-for-children/index.html) [Accessed October 8 2018]

26

Okada HLow KLKohanbash GMcDonald HAHamilton RLPollack IF: Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas. J Neurooncol 88:2452502008

27

Pollack IF: Brain tumors in children. N Engl J Med 331:150015071994

28

Souweidane MMKramer KPandit-Taskar NZhou ZHaque SZanzonico P: Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial. Lancet Oncol 19:104010502018

29

Souweidane MMOcchiogrosso GMark EBEdgar MA: Interstitial infusion of IL13-PE38QQR in the rat brain stem. J Neurooncol 67:2872932004

30

Truffaux NPhilippe CPaulsson JAndreiuolo FGuerrini-Rousseau LCornilleau G: Preclinical evaluation of dasatinib alone and in combination with cabozantinib for the treatment of diffuse intrinsic pontine glioma. Neuro Oncol 17:9539642015

31

Tzika AAAstrakas LGZarifi MKZurakowski DPoussaint TYGoumnerova L: Spectroscopic and perfusion magnetic resonance imaging predictors of progression in pediatric brain tumors. Cancer 100:124612562004

32

Wolters PLMartin SMerker VLGardner KLHingtgen CMTonsgard JH: Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials. Neurology 81 (21 Suppl 1):S6S142013

33

Wolters PLMartin STamula MAWiener LPerez LAikin A: Development of a quality of life scale for children with chronic illness with CNS involvement: preliminary data. Neuro Oncol 6:4484492004 (Abstract)

34

Wood JDLonser RRGogate NMorrison PFOldfield EH: Convective delivery of macromolecules into the naive and traumatized spinal cords of rats. J Neurosurg 90 (1 Suppl):1151201999

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