Interleukin-13 receptor as a unique target for anti-glioblastoma therapy

Surgery, radiotherapy and chemotherapy have minimally altered survival of g lioblastoma patients. We explored a specific approach for glioblastoma ther apy in which cellular interleukin-13 (IL-13) receptors were targeted by an IL-13 cytotoxin. A wide array of human glioblastoma cell lines expressing t he receptor for IL-13 were effectively killed by an IL-13 cytotoxin, a chim eric protein composed of human IL-13 and a mutated form of Pseudomonas exot oxin (termed IL13-PE38QQR or IL-13 toxin). Daily (qd) intratumoral injectio ns of IL-13 toxin (50 and 100 mug/kg/day) for 5 consecutive days into subcu taneous human U251 glioblastoma tumors (approx. 30 mm(2)) in nude mice resu lted in complete regression of tumors in 4/5 and 5/5 mice, respectively. Tu mor regression persisted for at least 221 days postimplantation. Three alte rnate day injections (qod) of IL-13 toxin (250 mug/kg/day) into other subcu taneous U87 glioblastoma tumors also produced durable complete responses (C R) in all 5 mice. Twice daily (bid) intraperitoneal injections of IL-13 tox in at 25 or 50 mug/kg/dose for 5 days (total doses = 10) regressed U251 tum ors by 45% and 58% with 1/5 and 2/5 CRs, respectively, on day 54. Intraperi toneal administration of IL-13 toxin with an identical schedule at a dose o f 50 mug/kg injected into mice bearing U87 xenografts reduced tumor burden by one-half on day 36. Similar doses (25 or 50 mug/kg) with a daily schedul e (qd x 5) by the intravenous route also suppressed growth of U251 subcutan eous 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-PE3 8QQR in patients with recurrent glioblastoma. Published 2001 Wiley-Liss, In c.(dagger).