Convection enhanced delivery of IL13-PE38QQR for treatment of recurrent malignant glioma: presentation of interim findings from ongoing phase 1 studies.
IL13PE38QQR is a recombinant toxin composed of the enzymatically-active portion of Pseudomonas Exotoxin A conjugated with human IL13. Binding of IL13-PE38 to the IL13 receptor (IL13R) permits internalization of the recombinant toxin resulting in selective and potent cytoxicity at nanomolar concentrations. Normal brain tissue expresses little or no IL13R, but malignant gliomas overexpress IL13R conferring the selective cytotoxicity to the agent. Convection-enhanced delivery (CED), a novel direct drug delivery method to tumor and peritumoral region uses positive pressure infusion to generate a pressure gradient that optimizes distribution of macromolecules within the brain. Three phase I studies have been initiated to investigate IL13-PE38QQR as an anti-tumor agent for the treatment of patients with recurrent malignant gliomas. As of January 2003 a total of 46 patients have been treated. The presentation at the March 2003 EANS Local Therapy of Glioma meeting reflects adverse event findings through January 2003 and survival data through March 2003. Intratumoral infusion with or without resection is fairly well-tolerated with corticosteroids prophylaxis particularly for patients with raised intracranial pressure. Post-resection infusion into the peritumoral brain parenchyma also appears to be very well tolerated. Histopathological tumor effect was seen at drug concentrations of 0.5-2.0 microg/mL. Although phase I studies do not focus on efficacy evaluation, prolonged survival times have been observed in this select population of patients. The preclinical data and details and preliminary results of the three clinical trials are reviewed.
Kunwar
S
S
Department of Neurological Surgery, University of California, San Francisco, CA 94143-0112, USA. kunwars@neurosurg.ucsf.edu
D000328:Adult; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D002470:Cell Survival / Q000187:drug effects; D017321:Clinical Trials, Phase I as Topic; D017322:Clinical Trials, Phase II as Topic; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004358:Drug Therapy; D005098:Exotoxins; D005910:Glioma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000601:surgery; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000009:adverse effects; D036502:Infusions, Intralesional; D018793:Interleukin-13 / Q000008:administration & dosage*; D020360:Neoadjuvant Therapy; D011993:Recombinant Fusion Proteins; D015996:Survival Rate; D014410:Tumor Stem Cell Assay
D005098:Exotoxins; C521502:IL13-PE38; D000922:Immunotoxins; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins