title: Intratumoral administration of recombinant circularly permuted interleukin-4-Pseudomonas exotoxin in patients with high-grade glioma.
abstract: Human glioblastoma but not normal brain cells express numerous receptors for the cytokine interleukin (IL)-4. To target these receptors, we have investigated the safety and activity of directly infusing IL-4(38-37)-PE38KDEL, a chimeric protein composed of circularly permuted IL-4 and a truncated form of Pseudomonas exotoxin (PE), into recurrent malignant high-grade gliomas. IL-4(38-37)-PE38KDEL (IL-4-toxin) was infused over a 4-8-day period into gliomas of nine patients by one to three stereotactically placed catheters. No apparent systemic toxicity occurred in any patient. The infusion of IL-4-toxin in six of nine patients showed glioma necrosis as evidenced by diminished gadolinium enhancement on magnetic resonance imaging. Seven of nine patients underwent craniotomy because of increased intracranial pressure at 16-101 days after the beginning of infusion. In six of these seven patients, partial-to-extensive tumor necrosis with edema was confirmed pathologically. No histological evidence of neurotoxicity to normal brain was identified in any patient. Two patients were not operated on; by magnetic resonance imaging, one showed mottled gadolinium enhancement, and the other showed extensive necrosis of tumor leading to complete remission; this patient remains disease-free > 18 months after the procedure. We conclude that direct glioma injection of IL-4(38-37)-PE38KDEL is safe without systemic toxicity. Local toxicity seemed attributable mainly to tumor necrosis or occasionally to the volume of infusion. Histological evidence of toxicity to normal brain was not observed and in many patients, could be pathologically excluded. Additional patients are being treated to determine the maximal tolerated concentration and volume of IL-4(38-37)-PE38KDEL.
authors.affiliation: Department of Neuro-Oncology, John Wayne Cancer Institute, Santa Monica, California 90404, USA.
authors.forename: R W
authors.initials: RW
authors.lastname: Rand
authors.forename: R J
authors.initials: RJ
authors.lastname: Kreitman
authors.forename: N
authors.initials: N
authors.lastname: Patronas
authors.forename: F
authors.initials: F
authors.lastname: Varricchio
authors.forename: I
authors.initials: I
authors.lastname: Pastan
authors.forename: R K
authors.initials: RK
authors.lastname: Puri
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000139:chemically induced; D005098:Exotoxins / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D005682:Gadolinium / Q000737:chemistry; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D000922:Immunotoxins / Q000008:administration & dosage* / Q000627:therapeutic use* / Q000633:toxicity; D015847:Interleukin-4 / Q000008:administration & dosage / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D011549:Pseudomonas / Q000737:chemistry*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use* / Q000633:toxicity; D013997:Time Factors; D014055:Tomography, Emission-Computed
chemical_list: D005098:Exotoxins; D000922:Immunotoxins; D011993:Recombinant Fusion Proteins; C120228:interleukin 4 (38-37)-PE38KDEL; D015847:Interleukin-4; D005682:Gadolinium