Interstitial infusion of glioma-targeted recombinant immunotoxin 8H9scFv-PE38 Journal Article

Authors: Luther, N.; Cheung, N. K.; Souliopoulos, E. P.; Karempelas, I.; Bassiri, D.; Edgar, M. A.; Guo, H. F. ; Pastan, I.; Gutin, P. H.; Souweidane, M. M.
Article Title: Interstitial infusion of glioma-targeted recombinant immunotoxin 8H9scFv-PE38
Abstract: Monoclonal antibodies have the potential to target therapy for high-grade gliomas. Monoclonal antibody 8H9 is specific for membrane protein B7H3 and is reactive with most human high-grade gliomas. We tested the 8H9scFv-PE38 recombinant Pseudomonas immunotoxin in a preclinical model of high-grade glioma. The half maximal inhibitory concentration (IC50) of 8H9scFv-PE38 in vitro was determined using glioblastoma cell lines U87 and U251. Maximum tolerated infusion dose of 8H9scFv-PE38 following interstitial infusion to the striatum and pons was defined using athymic rats. Maximum tolerated infusion dose of 8H9scFv-PE38 or PBS control were interstitially delivered to athymic rats xenografted with U87 in the striatum or brain stem. Radiographic response and survivals were measured and compared between treatment groups. The in vitro IC50 of 8H9scFv-PE38 for U87 was 1,265 ng/mL and, for U251, 91 ng/mL. The maximum tolerated infusion doses of interstitially infused 8H9scFv-PE38 to the striatum and brain stem were 0.75 and 1.8 μg, respectively. For rats harboring intracranial U87 xenografts, infusion of 8H9scFv-PE38 increased mean survival (striatum, 43.4 versus 24.6 days; brain stem, 80.6 versus 45.5 days; n = 28 total) and produced three long-term survivors past 120 days. None of the 14 placebo-treated animals survived >54 days. Tumors also showed volumetric response to infusion of 8H9scFv-PE38 by magnetic resonance imaging. Interstitial infusion of 8H9scFv-PE38 shows potential for the treatment of hemispherical and brain stem glioma. © 2010 AACR.
Keywords: controlled study; treatment outcome; human cell; drug efficacy; nonhuman; nuclear magnetic resonance imaging; glioma; cell proliferation; animal cell; animals; animal tissue; cell death; animal experiment; animal model; antineoplastic activity; cytotoxicity; in vitro study; tumor xenograft; xenograft model antitumor assays; cell line, tumor; kaplan-meiers estimate; antibodies, monoclonal; recombinant proteins; recombinant protein; rat; rats; maximum tolerated dose; brain stem; immunotoxin; immunotoxins; infusions, intralesional
Journal Title: Molecular Cancer Therapeutics
Volume: 9
Issue: 4
ISSN: 1535-7163
Publisher: American Association for Cancer Research  
Date Published: 2010-04-01
Start Page: 1039
End Page: 1046
Language: English
DOI: 10.1158/1535-7163.mct-09-0996
PUBMED: 20371725
PROVIDER: scopus
PMCID: PMC4077038
Notes: --- - "Export Date: 20 April 2011" - "CODEN: MCTOC" - "Source: Scopus"
Citation Impact
MSK Authors
  1. Nai-Kong Cheung
    569 Cheung
  2. Philip H Gutin
    162 Gutin
  3. Mark Allen Edgar
    45 Edgar
  4. Hong-Fen Guo
    54 Guo