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  • Antitumor efficacy of D2C7-(scdsFv)-PE38KDEL, a novel immunotoxin targeting EGFRwt and EGFRvIII, by convection-enhanced delivery in orthotopic brain tumor mouse models

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Poster Presentation
Antitumor efficacy of D2C7-(scdsFv)-PE38KDEL, a novel immunotoxin targeting EGFRwt and EGFRvIII, by convection-enhanced delivery in orthotopic brain tumor mouse models
  1. Xuhui Bao1,2,
  2. Vidyalakshmi Chandramohan1,
  3. Stephen T Keir1,
  4. Charles N Pegram1,
  5. Roger E McLendon1,
  6. Chien-Tsun Kuan1,
  7. Ira H Pastan3 and
  8. Darell D Bigner1
  1. Aff1 PathologyPreston Robert Tisch Brain Tumor Center Durham NC USA
  2. Aff2 grid.8547.e0000000101252443Neurosurgery, Huashan HospitalFudan University Shanghai China
  3. Aff3 grid.48336.3a0000000419368075Laboratory of Molecular Biology, Center for Cancer ResearchNational Cancer Institute, National Institutes of Health Bethesda MD USA

http://dx.doi.org/10.1186/2051-1426-1-S1-P126

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    Meeting abstracts

    Objective

    The epidermal growth factor receptor (EGFR) gene is most frequently amplified and overexpressed, along with its truncated mutant, EGFRvIII, in glioblastomas. We tested the antitumor efficacy of the recombinant immunotoxin, D2C7-(scdsFv)-PE38KDEL (D2C7-IT), which is reactive with a 55-amino acid (AA) region present in the extracellular domain of both EGFRwt and EGFRvIII proteins (Figure 1), by convection-enhanced delivery (CED) in orthotopic brain tumor mouse models established with human glioblastoma xenograft cells.

    Figure 1
    Figure 1

    Kaplan-Meier survival curves of different brain tumor models and the immunotoxin killing paradigm

    Methods

    Orthotopic brain tumor models were established by inoculating 43 (EGFRwt expressing glioma cell), D270MG (EGFRwt and EGFRvIII espressing glioma cells), and NR6M (EGFRvIII expressing fibroblast cells) intracranially in the immunocompromised mice. CED was achieved by inserting a cannula into the brain tumor site, which in turn was connected to a subcutaneous osmotic pump delivering the immunotoxin into the tumor microenvironment. The antitumor efficacy was evaluated by Kaplan-Meier survival analysis.

    Results

    In the orthotopic brain tumor models of 43, NR6M, and D270MG, D2C7-IT therapy via CED significantly prolonged the median survival time (MST) of the treatment group by about 1 month (P=0.0010), 1 week (P=0.0074), and over 1 month (P=0.0061), respectively, compared with that of vehicle or negative control groups (Table 1, Figure 1).

    View this table:

    Comparison of MST among different groups in three xenograft mouse models

    Conclusion

    In the orthotopic brain tumor mouse models, the D2C7-IT therapy via CED exhibited a robust therapeutic potential in treating brain tumors expressing EGFRwt, EGFRvIII, and both EGFRwt and EGFRvIII.