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Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1.

Publication ,  Journal Article
Archer, GE; Sampson, JH; Lorimer, IA; McLendon, RE; Kuan, CT; Friedman, AH; Friedman, HS; Pastan, IH; Bigner, DD
Published in: Clin Cancer Res
September 1999

The incidence of neoplastic meningitis is on the rise. Neoplastic meningitis can result from a direct seeding of the neuraxis by primary brain tumors or by hematogeneous spread of systemic solid tumors. A frequent genetic alteration in primary brain tumors such as gliomas is an in-frame deletion in the epidermal growth factor receptor (EGFR) gene EGFRvIII, which brings together what were normally distant polypeptide sequences in the intact receptor. A novel glycine is formed at the fusion junction, resulting in a unique and tumor-specific target. By using phage display, we have isolated a single-chain antibody specific for the EGFRvIII mutation and expressed it with a modified form of the Pseudomonas exotoxin to form the immunotoxin MR1scFvPE38KDEL (MR-1). The multiple dose toxicity and therapeutic efficacy of MR-1 immunotoxin were tested in an athymic rat model of neoplastic meningitis. The maximally tolerated doses in non-tumor-bearing rats were three doses of 3 microg each. For therapeutic studies, the target was a neoplastic meningitis induced by intrathecal inoculation of the EGFRvIII-expressing human glioma U87MG.deltaEGFR. A dose escalation study compared the survival of three equal doses of 1, 2, and 3 microg of MR-1 immunotoxin with saline or 3 microg of the control immunotoxin specific for the interleukin 2 receptor, anti-Tac. All animals treated with three doses of saline or 3 microg of anti-Tac died, with median survival of 7 and 10 days, respectively. There were 75% (six of eight) long-term survivors in the group treated with three doses of 1 microg and 57% (four of seven) long-term survivors in the groups treated with three doses of either 2 or 3 microg of MR-1 immunotoxin. None of the MR-1 immunotoxin-treated groups reached median survival by the termination of the study at 53 days. Therefore, median survival was estimated to be >53 days, resulting in an estimated increase in median survival of >657% compared with saline and 430% versus anti-Tac. Compartmental therapy with three doses of 2 microg of MR-1 immunotoxin is effective in the treatment of EGFRvIII-expressing neoplastic meningitis. This dose was found to have no clinical or histopathological effects on non-tumor-bearing animals. MR-1 immunotoxin is, therefore, considered specific and safe within its therapeutic window. Phase I clinical trials for tumors invading the intrathecal space that express the EGFRvIII target should be initiated.

Duke Scholars

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

September 1999

Volume

5

Issue

9

Start / End Page

2646 / 2652

Location

United States

Related Subject Headings

  • Virulence Factors
  • Tumor Cells, Cultured
  • Rats, Nude
  • Rats
  • Pseudomonas aeruginosa Exotoxin A
  • Protein Synthesis Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Mice, Nude
  • Mice
 

Citation

APA
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ICMJE
MLA
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Archer, G. E., Sampson, J. H., Lorimer, I. A., McLendon, R. E., Kuan, C. T., Friedman, A. H., … Bigner, D. D. (1999). Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1. Clin Cancer Res, 5(9), 2646–2652.
Archer, G. E., J. H. Sampson, I. A. Lorimer, R. E. McLendon, C. T. Kuan, A. H. Friedman, H. S. Friedman, I. H. Pastan, and D. D. Bigner. “Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1.Clin Cancer Res 5, no. 9 (September 1999): 2646–52.
Archer GE, Sampson JH, Lorimer IA, McLendon RE, Kuan CT, Friedman AH, et al. Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1. Clin Cancer Res. 1999 Sep;5(9):2646–52.
Archer GE, Sampson JH, Lorimer IA, McLendon RE, Kuan CT, Friedman AH, Friedman HS, Pastan IH, Bigner DD. Regional treatment of epidermal growth factor receptor vIII-expressing neoplastic meningitis with a single-chain immunotoxin, MR-1. Clin Cancer Res. 1999 Sep;5(9):2646–2652.

Published In

Clin Cancer Res

ISSN

1078-0432

Publication Date

September 1999

Volume

5

Issue

9

Start / End Page

2646 / 2652

Location

United States

Related Subject Headings

  • Virulence Factors
  • Tumor Cells, Cultured
  • Rats, Nude
  • Rats
  • Pseudomonas aeruginosa Exotoxin A
  • Protein Synthesis Inhibitors
  • Oncology & Carcinogenesis
  • Mutation
  • Mice, Nude
  • Mice