Advertisement

Journal of Neuro-Oncology

, Volume 98, Issue 1, pp 1–7 | Cite as

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

  • Dale Ding
  • Charles W. Kanaly
  • Darrell D. Bigner
  • Thomas J. Cummings
  • James E. HerndonII
  • Ira Pastan
  • Raghu Raghavan
  • John H. SampsonEmail author
Laboratory Investigation - Human/Animal Tissue

Abstract

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. 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) 0.1 μmol/ml Gd-DTPA; (3) 25 ng/ml MR1-1 and 0.1 μmol/ml Gd-DTPA; (4) 250 ng/ml MR1-1 and 0.1 μmol/ml Gd-DTPA. The rats were monitored clinically for 6 weeks then necropsied and histologically assessed for CNS toxicity. 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). 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.

Keywords

Immunotoxins Brain Drug delivery systems glioblastoma Gadolinium 

Notes

Acknowledgements

We acknowledge the expert technical assistance provided by Gary Archer, Tracy Chewning, and April Coan. This research was supported in part by Duke University’s CTSA grant TL1RR024126 from National Center for Research Resources, National Institutes of Health and by the Intramural Research Program of the National Institutes of Health, National Cancer Institute, Center for Cancer Research.

References

  1. 1.
    Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci USA 91:2076–2080CrossRefPubMedGoogle Scholar
  2. 2.
    Sampson JH, Akabani G, Archer GE, Berger MS, Coleman RE, Friedman AH, Friedman HS, Greer K, Herndon JE II, Kunwar S, McLendon RE, Paolino A, Petry NA, Provenzale JM, Reardon DA, Wong TZ, Zalutsky MR, Pastan I, Bigner DD (2008) Intracerebral infusion of an EGFR-targeted toxin in recurrent malignant brain tumors. Neuro Oncol 10:320–329CrossRefPubMedGoogle Scholar
  3. 3.
    Vogelbaum MA (2007) Convection enhanced delivery for treating brain tumors and selected neurological disorders: symposium review. J Neurooncol 83:97–109CrossRefPubMedGoogle Scholar
  4. 4.
    Weaver M, Laske DW (2003) Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 65:3–13CrossRefPubMedGoogle Scholar
  5. 5.
    Weber F, Asher A, Bucholz R, Berger M, Prados M, Chang S, Bruce J, Hall W, Rainov NG, Westphal M, Warnick RE, Rand RW, Floeth F, Rommel F, Pan H, Hingorani VN, Puri RK (2003) Safety, tolerability, and tumor response of IL4-Pseudomonas exotoxin (NBI-3001) in patients with recurrent malignant glioma. J Neurooncol 64:125–137PubMedGoogle Scholar
  6. 6.
    Vogelbaum MA, Sampson JH, Kunwar S, Chang SM, Shaffrey M, Asher AL, Lang FF, Croteau D, Parker K, Grahn AY, Sherman JW, Husain SR, Puri RK (2007) Convection-enhanced delivery of cintredekin besudotox (interleukin-13-PE38QQR) followed by radiation therapy with and without temozolomide in newly diagnosed malignant gliomas: phase 1 study of final safety results. Neurosurgery 61:1031–1037 discussion 1037-1038CrossRefPubMedGoogle Scholar
  7. 7.
    Bankiewicz KS, Eberling JL, Kohutnicka M, Jagust W, Pivirotto P, Bringas J, Cunningham J, Budinger TF, Harvey-White J (2000) Convection-enhanced delivery of AAV vector in parkinsonian monkeys; in vivo detection of gene expression and restoration of dopaminergic function using pro-drug approach. Exp Neurol 164:2–14CrossRefPubMedGoogle Scholar
  8. 8.
    Oiwa Y, Sanchez-Pernaute R, Harvey-White J, Bankiewicz KS (2003) Progressive and extensive dopaminergic degeneration induced by convection-enhanced delivery of 6-hydroxydopamine into the rat striatum: a novel rodent model of Parkinson disease. J Neurosurg 98:136–144CrossRefPubMedGoogle Scholar
  9. 9.
    Zirzow GC, Sanchez OA, Murray GJ, Brady RO, Oldfield EH (1999) Delivery, distribution, and neuronal uptake of exogenous mannose-terminal glucocerebrosidase in the intact rat brain. Neurochem Res 24:301–305CrossRefPubMedGoogle Scholar
  10. 10.
    Lonser RR, Schiffman R, Robison RA, Butman JA, Quezado Z, Walker ML, Morrison PF, Walbridge S, Murray GJ, Park DM, Brady RO, Oldfield EH (2007) Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology 68:254–261CrossRefPubMedGoogle Scholar
  11. 11.
    Lonser RR, Walbridge S, Murray GJ, Aizenberg MR, Vortmeyer AO, Aerts JM, Brady RO, Oldfield EH (2005) Convection perfusion of glucocerebrosidase for neuronopathic Gaucher’s disease. Ann Neurol 57:542–548CrossRefPubMedGoogle Scholar
  12. 12.
    Fisher RS, Ho J (2002) Potential new methods for antiepileptic drug delivery. CNS Drugs 16:579–593CrossRefPubMedGoogle Scholar
  13. 13.
    Fisher RS, Chen DK (2006) New routes for delivery of anti-epileptic medications. Acta Neurol Taiwan 15:225–231PubMedGoogle Scholar
  14. 14.
    Primary brain tumors in the United States statistical report. Central Brain Tumor Registry of the United States, HinsdaleGoogle Scholar
  15. 15.
    Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996CrossRefPubMedGoogle Scholar
  16. 16.
    Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC, Stupp R (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003CrossRefPubMedGoogle Scholar
  17. 17.
    Humphrey PA, Wong AJ, Vogelstein B, Zalutsky MR, Fuller GN, Archer GE, Friedman HS, Kwatra MM, Bigner SH, Bigner DD (1990) Anti-synthetic peptide antibody reacting at the fusion junction of deletion-mutant epidermal growth factor receptors in human glioblastoma. Proc Natl Acad Sci USA 87:4207–4211CrossRefPubMedGoogle Scholar
  18. 18.
    Chu CT, Everiss KD, Wikstrand CJ, Batra SK, Kung HJ, Bigner DD (1997) Receptor dimerization is not a factor in the signalling activity of a transforming variant epidermal growth factor receptor (EGFRvIII). Biochem J 324(Pt 3):855–861PubMedGoogle Scholar
  19. 19.
    Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, Biegel JA, Hayes RL, Wong AJ (1995) Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Res 55:5536–5539PubMedGoogle Scholar
  20. 20.
    Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, Kurpad SN, McLendon RE, Moscatello D, Pegram CN, Reist CJ et al (1995) Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and malignant gliomas. Cancer Res 55:3140–3148PubMedGoogle Scholar
  21. 21.
    Pastan I, FitzGerald D (1991) Recombinant toxins for cancer treatment. Science 254:1173–1177CrossRefPubMedGoogle Scholar
  22. 22.
    Pastan I, Chaudhary V, FitzGerald DJ (1992) Recombinant toxins as novel therapeutic agents. Annu Rev Biochem 61:331–354CrossRefPubMedGoogle Scholar
  23. 23.
    Ochiai H, Archer GE, Herndon JE II, Kuan CT, Mitchell DA, Bigner DD, Pastan IH, Sampson JH (2008) EGFRvIII-targeted immunotoxin induces antitumor immunity that is inhibited in the absence of CD4+ and CD8+ T cells. Cancer Immunol Immunother 57:115–121CrossRefPubMedGoogle Scholar
  24. 24.
    Sampson JH, Brady ML, Petry NA, Croteau D, Friedman AH, Friedman HS, Wong T, Bigner DD, Pastan I, Puri RK, Pedain C (2007) Intracerebral infusate distribution by convection-enhanced delivery in humans with malignant gliomas: descriptive effects of target anatomy and catheter positioning. Neurosurgery 60:ONS89–ONS98 discussion ONS98-89CrossRefPubMedGoogle Scholar
  25. 25.
    Sampson JH, Raghavan R, Provenzale JM, Croteau D, Reardon DA, Coleman RE, Rodriguez Ponce I, Pastan I, Puri RK, Pedain C (2007) Induction of hyperintense signal on T2-weighted MR images correlates with infusion distribution from intracerebral convection-enhanced delivery of a tumor-targeted cytotoxin. AJR Am J Roentgenol 188:703–709CrossRefPubMedGoogle Scholar
  26. 26.
    Mardor Y, Roth Y, Lidar Z, Jonas T, Pfeffer R, Maier SE, Faibel M, Nass D, Hadani M, Orenstein A, Cohen JS, Ram Z (2001) Monitoring response to convection-enhanced taxol delivery in brain tumor patients using diffusion-weighted magnetic resonance imaging. Cancer Res 61:4971–4973PubMedGoogle Scholar
  27. 27.
    Mardor Y, Rahav O, Zauberman Y, Lidar Z, Ocherashvilli A, Daniels D, Roth Y, Maier SE, Orenstein A, Ram Z (2005) Convection-enhanced drug delivery: increased efficacy and magnetic resonance image monitoring. Cancer Res 65:6858–6863CrossRefPubMedGoogle Scholar
  28. 28.
    Raghavan R, Brady ML, Rodriguez-Ponce MI, Hartlep A, Pedain C, Sampson JH (2006) Convection-enhanced delivery of therapeutics for brain disease, and its optimization. Neurosurg Focus 20:E12CrossRefPubMedGoogle Scholar
  29. 29.
    Nguyen TT, Pannu YS, Sung C, Dedrick RL, Walbridge S, Brechbiel MW, Garmestani K, Beitzel M, Yordanov AT, Oldfield EH (2003) Convective distribution of macromolecules in the primate brain demonstrated using computerized tomography and magnetic resonance imaging. J Neurosurg 98:584–590CrossRefPubMedGoogle Scholar
  30. 30.
    Murad GJ, Walbridge S, Morrison PF, Garmestani K, Degen JW, Brechbiel MW, Oldfield EH, Lonser RR (2006) Real-time, image-guided, convection-enhanced delivery of interleukin 13 bound to pseudomonas exotoxin. Clin Cancer Res 12:3145–3151CrossRefPubMedGoogle Scholar
  31. 31.
    Lonser RR, Walbridge S, Garmestani K, Butman JA, Walters HA, Vortmeyer AO, Morrison PF, Brechbiel MW, Oldfield EH (2002) Successful and safe perfusion of the primate brainstem: in vivo magnetic resonance imaging of macromolecular distribution during infusion. J Neurosurg 97:905–913CrossRefPubMedGoogle Scholar
  32. 32.
    Saito R, Krauze MT, Bringas JR, Noble C, McKnight TR, Jackson P, Wendland MF, Mamot C, Drummond DC, Kirpotin DB, Hong K, Berger MS, Park JW, Bankiewicz KS (2005) Gadolinium-loaded liposomes allow for real-time magnetic resonance imaging of convection-enhanced delivery in the primate brain. Exp Neurol 196:381–389CrossRefPubMedGoogle Scholar
  33. 33.
    Saito R, Bringas JR, McKnight TR, Wendland MF, Mamot C, Drummond DC, Kirpotin DB, Park JW, Berger MS, Bankiewicz KS (2004) Distribution of liposomes into brain and rat brain tumor models by convection-enhanced delivery monitored with magnetic resonance imaging. Cancer Res 64:2572–2579CrossRefPubMedGoogle Scholar
  34. 34.
    Perlstein B, Ram Z, Daniels D, Ocherashvilli A, Roth Y, Margel S, Mardor Y (2008) Convection-enhanced delivery of maghemite nanoparticles: increased efficacy and MRI monitoring. Neuro Oncol 10:153–161CrossRefPubMedGoogle Scholar
  35. 35.
    Szerlip NJ, Walbridge S, Yang L, Morrison PF, Degen JW, Jarrell ST, Kouri J, Kerr PB, Kotin R, Oldfield EH, Lonser RR (2007) Real-time imaging of convection-enhanced delivery of viruses and virus-sized particles. J Neurosurg 107:560–567CrossRefPubMedGoogle Scholar
  36. 36.
    Lonser RR, Warren KE, Butman JA, Quezado Z, Robison RA, Walbridge S, Schiffman R, Merrill M, Walker ML, Park DM, Croteau D, Brady RO, Oldfield EH (2007) Real-time image-guided direct convective perfusion of intrinsic brainstem lesions. Technical note. J Neurosurg 107:190–197CrossRefPubMedGoogle Scholar
  37. 37.
    Murad GJ, Walbridge S, Morrison PF, Szerlip N, Butman JA, Oldfield EH, Lonser RR (2007) Image-guided convection-enhanced delivery of gemcitabine to the brainstem. J Neurosurg 106:351–356CrossRefPubMedGoogle Scholar
  38. 38.
    Grossi PM, Ochiai H, Archer GE, McLendon RE, Zalutsky MR, Friedman AH, Friedman HS, Bigner DD, Sampson JH (2003) Efficacy of intracerebral microinfusion of trastuzumab in an athymic rat model of intracerebral metastatic breast cancer. Clin Cancer Res 9:5514–5520PubMedGoogle Scholar
  39. 39.
    Sampson JH, Raghavan R, Brady ML, Provenzale JM, Herndon JE II, Croteau D, Friedman AH, Reardon DA, Coleman RE, Wong T, Bigner DD, Pastan I, Rodriguez-Ponce MI, Tanner P, Puri R, Pedain C (2007) Clinical utility of a patient-specific algorithm for simulating intracerebral drug infusions. Neuro Oncol 9:343–353CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC. 2009

Authors and Affiliations

  • Dale Ding
    • 1
  • Charles W. Kanaly
    • 2
  • Darrell D. Bigner
    • 3
  • Thomas J. Cummings
    • 4
  • James E. HerndonII
    • 5
  • Ira Pastan
    • 6
  • Raghu Raghavan
    • 7
  • John H. Sampson
    • 8
    Email author
  1. 1.School of MedicineDuke University Medical Center, DUMCDurhamUSA
  2. 2.Division of Neurosurgery, Department of SurgeryDuke University Medical CenterDurhamUSA
  3. 3.Department of Pathology, Duke University Medical CenterThe Preston Robert Tisch Brain Tumor Center at DukeDurhamUSA
  4. 4.Department of PathologyDuke University Medical CenterDurhamUSA
  5. 5.Department of Biostatistics and BioinformaticsDuke University Medical CenterDurhamUSA
  6. 6.Laboratory of Molecular Biology, Center for Cancer Research, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  7. 7.Therataxis, LLCBaltimoreUSA
  8. 8.Division of Neurosurgery, Department of SurgeryDuke University Medical Center, The Preston Robert Tisch Brain Tumor Center at DukeDurhamUSA

Personalised recommendations