Interleukin-13 receptor as a unique target for anti-glioblastoma therapy.
Surgery, radiotherapy and chemotherapy have minimally altered survival of glioblastoma patients. We explored a specific approach for glioblastoma therapy in which cellular interleukin-13 (IL-13) receptors were targeted by an IL-13 cytotoxin. A wide array of human glioblastoma cell lines expressing the receptor for IL-13 were effectively killed by an IL-13 cytotoxin, a chimeric protein composed of human IL-13 and a mutated form of Pseudomonas exotoxin (termed IL13-PE38QQR or IL-13 toxin). Daily (qd) intratumoral injections of IL-13 toxin (50 and 100 microg/kg/day) for 5 consecutive days into subcutaneous human U251 glioblastoma tumors (approx. 30 mm(2)) in nude mice resulted in complete regression of tumors in 4/5 and 5/5 mice, respectively. Tumor regression persisted for at least 221 days postimplantation. Three alternate day injections (qod) of IL-13 toxin (250 microg/kg/day) into other subcutaneous U87 glioblastoma tumors also produced durable complete responses (CR) in all 5 mice. Twice daily (bid) intraperitoneal injections of IL-13 toxin at 25 or 50 microg/kg/dose for 5 days (total doses = 10) regressed U251 tumors by 45% and 58% with 1/5 and 2/5 CRs, respectively, on day 54. Intraperitoneal administration of IL-13 toxin with an identical schedule at a dose of 50 microg/kg injected into mice bearing U87 xenografts reduced tumor burden by one-half on day 36. Similar doses (25 or 50 microg/kg) with a daily schedule (qd x 5) by the intravenous route also suppressed growth of U251 subcutaneous tumors by 75% and 81% with 1/6 CR in either group by day 34. All mice tolerated therapy well without any visible signs of toxicity. On the basis of these studies, we have initiated a Phase I clinical trial using IL13-PE38QQR in patients with recurrent glioblastoma. Published 2001 Wiley-Liss, Inc.
Husain
S R
SR
Laboratory of Molecular Tumor Biology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Building 29B, 29 Lincoln Dr., Bethesda 20892, MD, USA.
Joshi
B H
BH
Puri
R K
RK
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D001932:Brain Neoplasms / Q000188:drug therapy; D002455:Cell Division / Q000187:drug effects; D005098:Exotoxins / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D005909:Glioblastoma / Q000473:pathology / Q000628:therapy*; D006801:Humans; D015552:Injections, Intralesional; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D018793:Interleukin-13 / Q000235:genetics / Q000627:therapeutic use*; D053661:Interleukin-13 Receptor alpha1 Subunit; D007700:Kinetics; D051379:Mice; D008819:Mice, Nude; D018123:Receptors, Interleukin / Q000378:metabolism*; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D037521:Virulence Factors; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D018123:Receptors, Interleukin; D053660:Receptors, Interleukin-13; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C508181:IL13RA1 protein, human; C508183:Il13ra1 protein, mouse