Complete regression of established human glioblastoma tumor xenograft by interleukin-4 toxin therapy

Cancer Res. 1998 Aug 15;58(16):3649-53.

Abstract

No curative therapy is available for malignant gliomas. We have discovered that human glioblastoma cells express high affinity interleukin-4 receptor (IL-4R), which is an attractive target for receptor-directed IL-4 toxin therapy. The IL-4 toxin, IL-4(38-37)-PE38KDEL, is a fusion protein containing translocation and enzymatic domains of Pseudomonas exotoxin and a circularly permuted human IL-4. The IL-4 toxin binds specifically to the IL-4R and is highly cytotoxic to glioblastoma cells, as determined by clonogenic and protein synthesis inhibition assays. Intratumoral administration of the IL-4 toxin given on alternate days for 3-4 doses into U251 glioblastoma flank tumors in nude mice, showed a complete remission of small (approximately 13 mm3) and large (approximately 60 mm3) tumors in all animals, without any evidence of toxicity. A significant antitumor activity was also observed when the IL-4 toxin was administered via i.p. and i.v. routes. These results demonstrate that the IL-4 toxin may be a new therapeutic drug for the treatment of human glioblastoma. Therefore, we have begun a Phase I clinical trial with IL-4(38-37)-PE38KDEL for treatment of human glioblastoma.

MeSH terms

  • ADP Ribose Transferases*
  • Animals
  • Bacterial Toxins*
  • Exotoxins / administration & dosage
  • Exotoxins / chemistry
  • Exotoxins / therapeutic use*
  • Female
  • Glioblastoma / metabolism*
  • Glioblastoma / therapy*
  • Humans
  • Injections, Intralesional
  • Injections, Intraperitoneal
  • Injections, Intravenous
  • Interleukin-4 / administration & dosage
  • Interleukin-4 / chemistry
  • Interleukin-4 / therapeutic use*
  • Mice
  • Receptors, Interleukin-4 / metabolism*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Virulence Factors*

Substances

  • Bacterial Toxins
  • Exotoxins
  • Receptors, Interleukin-4
  • Virulence Factors
  • Interleukin-4
  • ADP Ribose Transferases
  • toxA protein, Pseudomonas aeruginosa