Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors

Abstract

We investigated regional therapy of recurrent malignant brain tumors with transferrin-CRM107, a conjugate of human transferrin (Tf) and a genetic mutant of diphtheria toxin (CRM107) that lacks native toxin binding. Physiological barriers to delivering proteins to tumor and surrounding infiltrated brain were circumvented with high-flow interstitial microinfusion. At least a 50% reduction in tumor volume on magnetic resonance imaging (MRI) occurred in 9 of 15 patients who could be evaluated (60%), including two complete responses. Peritumoral toxicity developed 1–4 weeks after treatment in three of three patients at 1.0 μg/ml, but in zero of nine patients treated at lower concentrations. No symptomatic systemic toxicity occurred. Regional perfusion with Tf-CRM107 produces tumor responses without systemic toxicity in patients with malignant brain tumors refractory to conventional therapy. Direct interstitial infusion can be used successfully to distribute a large protein in the tumor and infiltrated brain surrounding the tumor.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

References

  1. Walker, A.E., Robins, M. & Weinfeld, F.D. Epidemiology of brain tumors: The national survey of intracranial neoplasms. Neurology 35, 219–226 (1985).

    Article  CAS  Google Scholar 

  2. Mahaley, M.S., Jr., Mettlin, C., Natarajan, N., Laws, E.R., Jr. & Peace, B.B. National survey of patterns of care for brain-tumor patients. J. Neurosurg. 71, 826–836 (1989).

    Article  Google Scholar 

  3. Salcman, M. Epidemiology and factors affecting survival. in Malignant Cerebral Glioma. (ed. Apuzzo, M.L.J.) 95–110 (Am. Assoc. of Neural. Surgeons, Park Ridge, IL, 1990).

    Google Scholar 

  4. Larrick, J.W. & Cresswell, P. Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J. Supramol. Struct. 11, 579–586 (1979).

    Article  CAS  Google Scholar 

  5. Faulk, W.P., His, B.L. & Stevens, P.L. Transferrin and transferrin receptors in carcinoma of the breast. Lancet 11, 390–392 (1980).

    Article  Google Scholar 

  6. Trowbridge, I.S. & Omary, M.B. Human cell surface glycoprotein related to cell proliferation is the receptor for transferrin. Proc. Natl. Acad. Sci. USA 78, 3039–3043 (1981).

    Article  CAS  Google Scholar 

  7. Shindelman, A.E., Ortmeyer, A.E. & Sussman, H.H. Demonstration of the transferrin receptor in human breast cancer tissue: Potential marker for identifying dividing cells. Int. J. Cancer 27, 329–334 (1981).

    Article  CAS  Google Scholar 

  8. Klausner, R.D. et al. Receptor mediated endocytosis of transferrin in K562 cells. J. Biol. Chem. 258, 4715–4724 (1983).

    CAS  PubMed  Google Scholar 

  9. Gatter, K.C., Brown, G., Trowbridge, I.S., Woolston, R.E. & Mason, D.Y. Transferrin receptors in human tissues: Their distribution and possible clinical relevance. J. Clin. Pathol. 36, 539–545 (1983).

    Article  CAS  Google Scholar 

  10. Zovickian, J.G., Johnson, V.G. & Youle, R.J. Potent and specific killing of human malignant brain tumor cells by an anti-transferrin receptor antibody-ricin immunotoxin. J. Neurosurg. 66, 850–861 (1987).

    Article  CAS  Google Scholar 

  11. Recht, L., Torres, C.O., Smith, T.W., Raso, V. & Griffin, T.W. Transferrin receptor in normal and neoplastic brain tissue: Implications for brain-tumor immunotherapy. J. Neurosurg. 72, 941–945 (1990).

    Article  CAS  Google Scholar 

  12. Prior, R., Reifenberger, G. & Wechsler, W. Transferrin receptor expression in tumours of the human nervous system: Relation to tumour type, grading and tumour growth fraction. Virchows Archiv. A Pathol. Anat. 416, 491–496 (1990).

    Article  CAS  Google Scholar 

  13. Jeffries, W.A. et al. Transferrin receptor on endothelium of brain capillaries. Nature 312, 162–163 (1984).

    Article  Google Scholar 

  14. Connor, J.R. & Fine, R.E. The distribution of transferrin immunoreactivity in the rat central nervous system. Brain Res. 368, 319–328 (1986).

    Article  CAS  Google Scholar 

  15. Greenfield, L., Johnson, V.G. & Youle, R.J. Mutations in Diphtheria toxin separate binding from entry and amplify immunotoxin selectivity. Science 238, 536–539 (1987).

    Article  CAS  Google Scholar 

  16. Johnson, et al. Improved tumor specific immunotoxins in the treatment of CNS and leptomeningeal neoplasia. J. Neurosurg. 70, 240–248 (1989).

    Article  CAS  Google Scholar 

  17. Laske, D.W. llercil, O., Akbasak, A., Youle, R.J. & Oldfield, E.H. Efficacy of direct intra-tumoral therapy with targeted protein toxins for solid human gliomas in nude mice. J. Neurosurg. 80, 520–526 (1994).

    Article  CAS  Google Scholar 

  18. Garfield, J., Dayan, A.D. & Weller, R.O. Postoperative intracavitary chemotherapy of malignant supratentorial astrocytomas using BCNU. Clin. Oncol. 1, 213–222 (1975).

    CAS  PubMed  Google Scholar 

  19. Kroin, J.S. & Penn, R.D. Intracerebral chemotherapy: Chronic microinfusion of cisplatin. Neurosurgery 10, 349–354 (1982).

    Article  CAS  Google Scholar 

  20. Sendelbeck, S.L. & Urquhart, J. Spatial distribution of dopamine, methotrexate and antipyrine during continuous intracerebral microperfusion. Brain Res. 328, 251–258 (1985).

    Article  CAS  Google Scholar 

  21. Jain, R.K. Delivery of novel therapeutic agents in tumors: Physiological barrier and strategies. J. Natl. Cancer Inst. 81, 570–576 (1989).

    Article  CAS  Google Scholar 

  22. Brem, H. et al. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 345, 1008–1012 (1995).

    Article  CAS  Google Scholar 

  23. Bobo, R.H. et al. Convection-enhanced delivery of macromolecules in the brain. Proc. Natl. Acad. Sci. USA 91, 2076–2080 (1994).

    Article  CAS  Google Scholar 

  24. Morrison, P.F., Laske, D.W., Bobo, R.H., Oldfield, E.H. & Dedrick, R.L. High-flow microinfusion: Tissue penetration and pharmacodynamics. Am. J. Physiol. 266, R292–R305 (1994).

    CAS  PubMed  Google Scholar 

  25. Lieberman, D.M., Laske, D.W., Morrison, P.F., Bankiewicz, K.S. & Oldfield, E.H. Convection-enhanced distribution of large molecules in gray matter during interstitial drug infusion. J. Neurosurg. 82, 1021–1029 (1995).

    Article  CAS  Google Scholar 

  26. Karnofsky, D.A. et al. Triethylene melamine in the treatment of neoplastic disease. Arch. Intern. Med. 87, 477–516 (1951).

    Article  CAS  Google Scholar 

  27. Moolten, F.L. & Cooperband, S.R. Selective destruction of target cells by diphtheria toxin conjugated to antibody directed against antigens on the cells. Science 169, 68–70 (1970).

    Article  CAS  Google Scholar 

  28. Thorpe, P.E. et al. Toxicity of diphtheria toxin for lymphoblastoid cells is increased by conjugation to antilymphocytic globulin. Nature 271, 752–755 (1978).

    Article  CAS  Google Scholar 

  29. Gilliland, D.G. et al. Antibody-directed cytotoxic agents: Use of monoclonal antibody to direct the action of toxin A-chains to colorectal carcinoma cells. Proc. Natl. Acad. Sci. USA 77, 4539–4543 (1980).

    Article  CAS  Google Scholar 

  30. Krolick, K.A., Villemez, C., Isakson, P., Uhr, J.W. & Vitetta, E.S. Selective killing of normal or neoplastic B cells by antibodies coupled to the A chain of ricin. Proc. Natl. Acad. Sci. USA 77, 5419–5423 (1980).

    Article  CAS  Google Scholar 

  31. Youle, R.J. & Neville, D.M., Jr., Anti-thy 1. 2 monoclonal antibody linked to ricin is a potent cell-type-specific toxin. Proc. Natl. Acad. Sci. USA 77, 5483–5486 (1980).

    Article  CAS  Google Scholar 

  32. Trowbridge, I.S. & Domingo, D.L. Anti-transferrin receptor monoclonal antibody and toxin-antibody conjugates affect growth of human tumour cells. Nature 294, 171–173 (1981).

    Article  CAS  Google Scholar 

  33. Youle, R.J. & Colombatti, M. Monoclonal antibodies linked to toxic proteins for bone marrow transplantation and cancer therapy. in Monoclonal Antibodies in Cancer: Advances in Diagnosis and Treatment, (ed. Roth, J.A.) 173–213 (Futura Publishing Co., New York, 1986).

    Google Scholar 

  34. Pastan, I., Willingham, M.C. & Fitzgerald, D.J., Immunotoxins. Cell 47, 641–648 (1986).

    Article  CAS  Google Scholar 

  35. Vitetta, E.S., Fulton, R.J., May, R.D., Till, M. & Uhr, J.W. Redesigning nature's poisons to create anti-tumor reagents. Science 238, 1098–1104 (1987).

    Article  CAS  Google Scholar 

  36. Vitetta, E.S. et al. Phase I immunotoxin trial in patients with B-cell lymphoma. Cancer Res. 51, 4052–4058 (1991).

    CAS  Google Scholar 

  37. Grossbard, M.L. et al. Serotherapy of B-cell neoplasms with anti-B4-blocked ricin: A phase I trial of daily bolus infusion. Blood 79, 576–585 (1992).

    CAS  PubMed  Google Scholar 

  38. Hesketh, P. et al. Clinical activity of a cytotoxic fusion protein in the treatment of cutaneous T-cell lymphoma. J. Clin. Oncol. 11, 1682–1690 (1993).

    Article  CAS  Google Scholar 

  39. Spitler, L.E. et al. Therapy of patients with malignant melanoma using a monoclonal antimelanoma antibody-ricin A chain immunotoxin. Cancer Res. 47, 1717–1723 (1987).

    CAS  PubMed  Google Scholar 

  40. Weiner, L.M. et al. Phase I evaluation of an anti-breast carcinoma monoclonal antibody 260F9-recombinant ricin A chain immunoconjugate. Cancer Res. 49, 4062–4067 (1989).

    CAS  PubMed  Google Scholar 

  41. Rybak, S.M. & Youle, R.J. Clinical use of immunotoxins: Monoclonal antibodies conjugated to protein toxins. Immunol. Allergy Clin. N. Am. 11, 359–380 (1991).

    Google Scholar 

  42. Johnson, V., Wilson, D., Greenfield, L. & Youle, R. The role of the diphtheria toxin receptor in cytosol translocation. J. Biol. Chem. 263, 1295–1300 (1988).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Laske, D., Youle, R. & Oldfield, E. Tumor regression with regional distribution of the targeted toxin TF-CRM107 in patients with malignant brain tumors. Nat Med 3, 1362–1368 (1997). https://doi.org/10.1038/nm1297-1362

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1297-1362

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing