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Diphtheria toxin-based targeted toxin therapy for brain tumors

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Abstract

Targeted toxins (TT) are molecules that bind cell surface antigens or receptors such as the transferrin or interleukin-13 receptor that are overexpressed in cancer. After internalization, the toxin component kills the cell. These recombinant proteins consist of an antibody or carrier ligand coupled to a modified plant or bacterial toxin such as diphtheria toxin (DT). These fusion proteins are very effective against brain cancer cells that are resistant to radiation therapy and chemotherapy. TT have shown an acceptable profile for toxicity and safety in animal studies and early clinical trials have demonstrated a therapeutic response. This review summarizes the characteristics of DT-based TT, the animal studies in malignant brain tumors and early clinical trial results. Obstacles to the successful treatment of brain tumors include poor penetration into tumor, the immune response to DT and cancer heterogeneity.

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References

  1. Kreisl TN (2009) Chemotherapy for malignant gliomas. Semin Radiat Oncol 19(3):150–154

    Article  PubMed  Google Scholar 

  2. Van Meir EG, Hadjipanayis CG, Norden AD, Shu HK, Wen PY, Olson JJ (2010) Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin 60(3):166–193

    Article  PubMed  Google Scholar 

  3. Pastan I, Hassan R, Fitzgerald DJ, Kreitman RJ (2006) Immunotoxin therapy of cancer. Nat Rev Cancer 6(7):559–565

    Article  PubMed  CAS  Google Scholar 

  4. Yokota T, Milenic DE, Whitlow M, Schlom J (1992) Rapid tumor penetration of a single-chain Fv and comparison with other immunoglobulin forms. Cancer Res 52(12):3402–3408

    PubMed  CAS  Google Scholar 

  5. Jain RK (1989) Delivery of novel therapeutic agents in tumors: physiological barriers and strategies. J Natl Cancer Inst 81(8):570–576

    Article  PubMed  CAS  Google Scholar 

  6. Rustamzadeh E, Li C, Doumbia S, Hall WA, Vallera DA (2003) Targeting the over-expressed urokinase-type plasminogen activator receptor on glioblastoma multiforme. J Neurooncol 65(1):63–75

    Article  PubMed  Google Scholar 

  7. Hall WA (2001) Immunotoxin treatment of brain tumors. Methods Mol Biol 166:139–154

    PubMed  CAS  Google Scholar 

  8. Hall WA (1996) Immunotoxin therapy. Neurosurg Clin N Am 7(3):537–546

    PubMed  CAS  Google Scholar 

  9. Piascik P (1999) FDA approves fusion protein for treatment of lymphoma. J Am Pharm Assoc (Wash) 39(4):571–572

    CAS  Google Scholar 

  10. Lansigan F, Stearns DM, Foss F (2010) Role of denileukin diftitox in the treatment of persistent or recurrent cutaneous T-cell lymphoma. Cancer Manag Res 2:53–59

    PubMed  CAS  Google Scholar 

  11. Hall WA, Fodstad O (1992) Immunotoxins and central nervous system neoplasia. J Neurosurg 76(1):1–12

    Article  PubMed  CAS  Google Scholar 

  12. Bidros DS, Vogelbaum MA (2009) Novel drug delivery strategies in neuro-oncology. Neurotherapeutics 6(3):539–546

    Article  PubMed  CAS  Google Scholar 

  13. Siegall CB (1994) Targeted toxins as anticancer agents. Cancer 74(3 Suppl):1006–1012

    Article  PubMed  CAS  Google Scholar 

  14. Rustamzadeh E, Low WC, Vallera DA, Hall WA (2003) Immunotoxin therapy for CNS tumor. J Neurooncol 64(1–2):101–116

    PubMed  Google Scholar 

  15. Yamaizumi M, Mekada E, Uchida T, Okada Y (1978) One molecule of diphtheria toxin fragment A introduced into a cell can kill the cell. Cell 15(1):245–250

    Article  PubMed  CAS  Google Scholar 

  16. De Zoysa A, Efstratiou A, Hawkey PM (2005) Molecular characterization of diphtheria toxin repressor (dtxR) genes present in nontoxigenic Corynebacterium diphtheriae strains isolated in the United Kingdom. J Clin Microbiol 43(1):223–228. doi:10.1128/JCM.43.1.223-228.2005

    Article  PubMed  Google Scholar 

  17. Zovickian J, Johnson VG, Youle RJ (1987) Potent and specific killing of human malignant brain tumor cells by an anti-transferrin receptor antibody-ricin immunotoxin. J Neurosurg 66(6):850–861

    Article  PubMed  CAS  Google Scholar 

  18. Sandvig K, Olsnes S (1981) Rapid entry of nicked diphtheria toxin into cells at low pH. Characterization of the entry process and effects of low pH on the toxin molecule. J Biol Chem 256(17):9068–9076

    PubMed  CAS  Google Scholar 

  19. Naglich JG, Metherall JE, Russell DW, Eidels L (1992) Expression cloning of a diphtheria toxin receptor: identity with a heparin-binding EGF-like growth factor precursor. Cell 69(6):1051–1061

    Article  PubMed  CAS  Google Scholar 

  20. Greenfield L, Johnson VG, Youle RJ (1987) Mutations in diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. Science 238(4826):536–539

    Article  PubMed  CAS  Google Scholar 

  21. Boquet P, Silverman MS, Pappenheimer AM Jr (1977) Interaction of diphtheria toxin with mammalian cell membranes. Prog Clin Biol Res 17:501–509

    PubMed  CAS  Google Scholar 

  22. Frankel AE, Tagge EP, Willingham MC (1995) Clinical trials of targeted toxins. Semin Cancer Biol 6(5):307–317

    Article  PubMed  CAS  Google Scholar 

  23. Johnson VG, Wrobel C, Wilson D, Zovickian J, Greenfield L, Oldfield EH, Youle R (1989) Improved tumor-specific immunotoxins in the treatment of CNS and leptomeningeal neoplasia. J Neurosurg 70(2):240–248

    Article  PubMed  CAS  Google Scholar 

  24. Li YM, Hall WA (2011) Cell surface receptors in malignant glioma. Neurosurgery 69 (4):980-994; discussion 994. doi:10.1227/NEU.0b013e318220a672

    Google Scholar 

  25. Dano K, Andreasen PA, Grondahl-Hansen J, Kristensen P, Nielsen LS, Skriver L (1985) Plasminogen activators, tissue degradation, and cancer. Adv Cancer Res 44:139–266

    Article  PubMed  CAS  Google Scholar 

  26. Rao JS, Steck PA, Tofilon P, Boyd D, Ali-Osman F, Stetler-Stevenson WG, Liotta LA, Sawaya R (1994) Role of plasminogen activator and of 92-KDa type IV collagenase in glioblastoma invasion using an in vitro matrigel model. J Neurooncol 18(2):129–138

    Article  PubMed  CAS  Google Scholar 

  27. Mohanam S, Sawaya R, McCutcheon I, Ali-Osman F, Boyd D, Rao JS (1993) Modulation of in vitro invasion of human glioblastoma cells by urokinase-type plasminogen activator receptor antibody. Cancer Res 53(18):4143–4147

    PubMed  CAS  Google Scholar 

  28. Kreitman RJ, Pastan I (2006) Immunotoxins in the treatment of hematologic malignancies. Curr Drug Targets 7(10):1301–1311

    Article  PubMed  CAS  Google Scholar 

  29. Yamamoto M, Sawaya R, Mohanam S, Bindal AK, Bruner JM, Oka K, Rao VH, Tomonaga M, Nicolson GL, Rao JS (1994) Expression and localization of urokinase-type plasminogen activator in human astrocytomas in vivo. Cancer Res 54(14):3656–3661

    PubMed  CAS  Google Scholar 

  30. Mohanam S, Sawaya RE, Yamamoto M, Bruner JM, Nicholson GL, Rao JS (1994) Proteolysis and invasiveness of brain tumors: role of urokinase-type plasminogen activator receptor. J Neurooncol 22(2):153–160

    Article  PubMed  CAS  Google Scholar 

  31. Rustamzadeh E, Hall WA, Todhunter DA, Vallera VD, Low WC, Liu H, Panoskaltsis-Mortari A, Vallera DA (2007) Intracranial therapy of glioblastoma with the fusion protein DTAT in immunodeficient mice. Int J Cancer 120(2):411–419

    Article  PubMed  CAS  Google Scholar 

  32. Zurawski G, de Vries JE (1994) Interleukin 13, an interleukin 4-like cytokine that acts on monocytes and B cells, but not on T cells. Immunol Today 15(1):19–26

    Article  PubMed  CAS  Google Scholar 

  33. Minty A, Chalon P, Derocq JM, Dumont X, Guillemot JC, Kaghad M, Labit C, Leplatois P, Liauzun P, Miloux B et al (1993) Interleukin-13 is a new human lymphokine regulating inflammatory and immune responses. Nature 362(6417):248–250

    Article  PubMed  CAS  Google Scholar 

  34. Liu H, Jacobs BS, Liu J, Prayson RA, Estes ML, Barnett GH, Barna BP (2000) Interleukin-13 sensitivity and receptor phenotypes of human glial cell lines: non-neoplastic glia and low-grade astrocytoma differ from malignant glioma. Cancer Immunol Immunother 49(6):319–324

    Article  PubMed  CAS  Google Scholar 

  35. Debinski W, Obiri NI, Powers SK, Pastan I, Puri RK (1995) 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(11):1253–1258

    PubMed  CAS  Google Scholar 

  36. Bernard J, Treton D, Vermot-Desroches C, Boden C, Horellou P, Angevin E, Galanaud P, Wijdenes J, Richard Y (2001) Expression of interleukin 13 receptor in glioma and renal cell carcinoma: IL13Ralpha2 as a decoy receptor for IL13. Lab Invest 81(9):1223–1231

    Article  PubMed  CAS  Google Scholar 

  37. Debinski W, Gibo DM, Slagle B, Powers SK, Gillespie GY (1999) Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Int J Oncol 15(3):481–486

    PubMed  CAS  Google Scholar 

  38. Skinnider BF, Kapp U, Mak TW (2001) Interleukin 13: a growth factor in hodgkin lymphoma. Int Arch Allergy Immunol 126(4):267–276

    Article  PubMed  CAS  Google Scholar 

  39. Jiang H, Harris MB, Rothman P (2000) IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol 105(6 Pt 1):1063–1070

    Article  PubMed  CAS  Google Scholar 

  40. Maini A, Hillman G, Haas GP, Wang CY, Montecillo E, Hamzavi F, Pontes JE, Leland P, Pastan I, Debinski W, Puri RK (1997) Interleukin-13 receptors on human prostate carcinoma cell lines represent a novel target for a chimeric protein composed of IL-13 and a mutated form of Pseudomonas exotoxin. J Urol 158(3 Pt 1):948–953

    PubMed  CAS  Google Scholar 

  41. Ripley D, Shoup B, Majewski A, Chegini N (2004) Differential expression of interleukins IL-13 and IL-15 in normal ovarian tissue and ovarian carcinomas. Gynecol Oncol 92(3):761–768

    Article  PubMed  CAS  Google Scholar 

  42. Joshi BH, Kawakami K, Leland P, Puri RK (2002) Heterogeneity in interleukin-13 receptor expression and subunit structure in squamous cell carcinoma of head and neck: differential sensitivity to chimeric fusion proteins comprised of interleukin-13 and a mutated form of pseudomonas exotoxin. Clin Cancer Res 8(6):1948–1956

    PubMed  CAS  Google Scholar 

  43. Shimamura T, Husain SR, Puri RK (2006) The IL-4 and IL-13 pseudomonas exotoxins: new hope for brain tumor therapy. Neurosurg Focus 20(4):E11

    Article  PubMed  Google Scholar 

  44. Todhunter DA, Hall WA, Rustamzadeh E, Shu Y, Doumbia SO, Vallera DA (2004) A bispecific immunotoxin (DTAT13) targeting human IL-13 receptor (IL-13R) and urokinase-type plasminogen activator receptor (uPAR) in a mouse xenograft model. Protein Eng Des Sel 17(2):157–164

    Article  PubMed  CAS  Google Scholar 

  45. Rustamzadeh E, Vallera DA, Todhunter DA, Low WC, Panoskaltsis-Mortari A, Hall WA (2006) Immunotoxin pharmacokinetics: a comparison of the anti-glioblastoma bi-specific fusion protein (DTAT13) to DTAT and DTIL13. J Neurooncol 77(3):257–266

    Article  PubMed  CAS  Google Scholar 

  46. Gatter KC, Brown G, Trowbridge IS, Woolston RE, Mason DY (1983) Transferrin receptors in human tissues: their distribution and possible clinical relevance. J Clin Pathol 36(5):539–545

    Article  PubMed  CAS  Google Scholar 

  47. Hall WA, Godal A, Juell S, Fodstad O (1992) In vitro efficacy of transferrin-toxin conjugates against glioblastoma multiforme. J Neurosurg 76(5):838–844

    Article  PubMed  CAS  Google Scholar 

  48. Newman R, Domingo D, Trotter J, Trowbridge I (1983) Selection and properties of a mouse L-cell transformant expressing human transferrin receptor. Nature 304(5927):643–645

    Article  PubMed  CAS  Google Scholar 

  49. Hall WA, Myklebust A, Godal A, Nesland JM, Fodstad O (1994) In vivo efficacy of intrathecal transferrin-Pseudomonas exotoxin A immunotoxin against LOX melanoma. Neurosurgery 34 (4):649-655; discussion 655-646

    Google Scholar 

  50. Lesley J, Domingo DL, Schulte R, Trowbridge IS (1984) Effect of an anti-murine transferrin receptor-ricin A conjugate on bone marrow stem and progenitor cells treated in vitro. Exp Cell Res 150(2):400–407

    Article  PubMed  CAS  Google Scholar 

  51. Weaver M, Laske DW (2003) Transferrin receptor ligand-targeted toxin conjugate (Tf-CRM107) for therapy of malignant gliomas. J Neurooncol 65(1):3–13

    Article  PubMed  Google Scholar 

  52. Buonerba C, Di Lorenzo G, Marinelli A, Federico P, Palmieri G, Imbimbo M, Conti P, Peluso G, De Placido S, Sampson JH (2011) A comprehensive outlook on intracerebral therapy of malignant gliomas. Crit Rev Oncol Hematol 80(1):54–68. doi:10.1016/j.critrevonc.2010.09.001

    Article  PubMed  Google Scholar 

  53. Pai-Scherf LH, Villa J, Pearson D, Watson T, Liu E, Willingham MC, Pastan I (1999) Hepatotoxicity in cancer patients receiving erb-38, a recombinant immunotoxin that targets the erbB2 receptor. Clin Cancer Res 5(9):2311–2315

    PubMed  CAS  Google Scholar 

  54. Capone PM, Papsidero LD, Chu TM (1984) Relationship between antigen density and immunotherapeutic response elicited by monoclonal antibodies against solid tumors. J Natl Cancer Inst 72(3):673–677

    PubMed  CAS  Google Scholar 

  55. Gan HK, Kaye AH, Luwor RB (2009) The EGFRvIII variant in glioblastoma multiforme. J Clin Neurosci 16(6):748–754

    Article  PubMed  CAS  Google Scholar 

  56. Kreitman RJ, Pastan I (1995) Importance of the glutamate residue of KDEL in increasing the cytotoxicity of Pseudomonas exotoxin derivatives and for increased binding to the KDEL receptor. Biochem J 307(Pt 1):29–37

    PubMed  CAS  Google Scholar 

  57. Stish BJ, Oh S, Chen H, Dudek AZ, Kratzke RA, Vallera DA (2009) Design and modification of EGF4KDEL 7Mut, a novel bispecific ligand-directed toxin, with decreased immunogenicity and potent anti-mesothelioma activity. Br J Cancer 101(7):1114–1123. doi:10.1038/sj.bjc.6605297

    Article  PubMed  CAS  Google Scholar 

  58. Oh S, Stish BJ, Sachdev D, Chen H, Dudek AZ, Vallera DA (2009) A novel reduced immunogenicity bispecific targeted toxin simultaneously recognizing human epidermal growth factor and interleukin-4 receptors in a mouse model of metastatic breast carcinoma. Clin Cancer Res 15(19):6137–6147. doi:10.1158/1078-0432.CCR-09-0696

    Article  PubMed  CAS  Google Scholar 

  59. Hall WA (2009) Convection-enhanced delivery: neurosurgical issues. Curr Drug Targets 10(2):126–130

    Article  PubMed  CAS  Google Scholar 

  60. 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 I study of final safety results. Neurosurgery 61 (5):1031-1037; discussion 1037-1038

    Google Scholar 

  61. Oh S, Odland R, Wilson SR, Kroeger KM, Liu C, Lowenstein PR, Castro MG, Hall WA, Ohlfest JR (2007) Improved distribution of small molecules and viral vectors in the murine brain using a hollow fiber catheter. J Neurosurg 107(3):568–577. doi:10.3171/JNS-07/09/0568

    Article  PubMed  Google Scholar 

  62. Olson JJ, Zhang Z, Dillehay D, Stubbs J (2008) Assessment of a balloon-tipped catheter modified for intracerebral convection-enhanced delivery. J Neurooncol 89(2):159–168. doi:10.1007/s11060-008-9612-7

    Article  PubMed  Google Scholar 

  63. 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(3):703–709. doi:10.2214/AJR.06.0428

    Article  PubMed  Google Scholar 

  64. Sampson JH, Raghavan R, Brady ML, Provenzale JM, Herndon JE 2nd, 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(3):343–353. doi:10.1215/15228517-2007-007

    Article  PubMed  CAS  Google Scholar 

  65. Kunwar S, Chang S, Westphal M, Vogelbaum M, Sampson J, Barnett G, Shaffrey M, Ram Z, Piepmeier J, Prados M, Croteau D, Pedain C, Leland P, Husain SR, Joshi BH, Puri RK (2010) Phase III randomized trial of CED of IL13-PE38QQR vs Gliadel wafers for recurrent glioblastoma. Neuro Oncol 12(8):871–881. doi:10.1093/neuonc/nop054

    Article  PubMed  CAS  Google Scholar 

  66. Kawakami M, Kawakami K, Puri RK (2003) Interleukin-4-Pseudomonas exotoxin chimeric fusion protein for malignant glioma therapy. J Neurooncol 65(1):15–25

    Article  PubMed  Google Scholar 

  67. Rainov NG, Heidecke V (2004) Long term survival in a patient with recurrent malignant glioma treated with intratumoral infusion of an IL4-targeted toxin (NBI-3001). J Neurooncol 66(1–2):197–201

    Article  PubMed  CAS  Google Scholar 

  68. Rand RW, Kreitman RJ, Patronas N, Varricchio F, Pastan I, Puri RK (2000) Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma. Clin Cancer Res 6(6):2157–2165

    PubMed  CAS  Google Scholar 

  69. Kunwar S, Prados MD, Chang SM, Berger MS, Lang FF, Piepmeier JM, Sampson JH, Ram Z, Gutin PH, Gibbons RD, Aldape KD, Croteau DJ, Sherman JW, Puri RK (2007) 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(7):837–844

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article.

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  1. Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse, NY, 13210, USA

    Yan Michael Li & Walter A. Hall

  2. Section on Molecular Cancer Therapeutics, Department of Therapeutic Radiology-Radiation Oncology, University of Minnesota Masonic Cancer Center, MMC: 367, Minneapolis, MN, 55455, USA

    Daniel A. Vallera

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  1. Yan Michael Li
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Correspondence to Walter A. Hall.

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Li, Y.M., Vallera, D.A. & Hall, W.A. Diphtheria toxin-based targeted toxin therapy for brain tumors. J Neurooncol 114, 155–164 (2013). https://doi.org/10.1007/s11060-013-1157-8

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