title: EGFR/EGFRvIII-targeted immunotoxin therapy for the treatment of glioblastomas via convection-enhanced delivery.
abstract: Glioblastoma is the most aggressive malignant brain tumor among all primary brain and central nervous system tumors. The median survival time for glioblastoma patients given the current standard of care treatment (surgery, radiation, and chemotherapy) is less than 15 months. Thus, there is an urgent need to develop more efficient therapeutics to improve the poor survival rates of patients with glioblastoma. To address this need, we have developed a novel tumor-targeted immunotoxin (IT), D2C7-(scdsFv)-PE38KDEL (D2C7-IT), by fusing the single chain variable fragment (scFv) from the D2C7 monoclonal antibody (mAb) with thePseudomonasExotoxin (PE38KDEL). D2C7-IT reacts with both the wild-type epidermal growth factor receptor (EGFRwt) and EGFR variant III (EGFRvIII), two onco-proteins frequently amplified or overexpressed in glioblastomas. Surface plasmon resonance and flow cytometry analyses demonstrated a significant binding capacity of D2C7-IT to both EGFRwt and EGFRvIII proteins.In vitrocytotoxicity data showed that D2C7-IT can effectively inhibit protein synthesis and kill a variety of EGFRwt-, EGFRvIII-, and both EGFRwt- and EGFRvIII-expressing glioblastoma xenograft cells and human tumor cell lines. Furthermore, D2C7-IT exhibited a robust anti-tumor efficacy in orthotopic mouse glioma models when administered via intracerebral convection-enhanced delivery (CED). A preclinical toxicity study was therefore conducted to determine the maximum tolerated dose (MTD) and no-observed-adverse-effect-level (NOAEL) of D2C7-IT via intracerebral CED for 72 hours in rats. Based on this successful rat toxicity study, an Investigational New Drug (IND) application (#116855) was approved by the Food and Drug Administration (FDA), and is now in effect for a Phase I/II D2C7-IT clinical trial (D2C7 for Adult Patients with Recurrent Malignant Glioma, https://clinicaltrials.gov/ct2/show/NCT02303678). While it is still too early to draw conclusions from the trial, results thus far are promising.
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Xuhui
authors.initials: X
authors.lastname: Bao
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Preston Robert Tisch Brain Tumor Center at Duke and Department of Pathology, Duke University Medical Center, Durham, NC, 27710, USA.
authors.forename: Vidyalakshmi
authors.initials: V
authors.lastname: Chandramohan
keywords: Convection-enhanced delivery; D2C7-(scdsFv)-PE38KDEL; Epidermal growth factor receptor; Glioblastoma; Immunotoxin