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Interleukin-13 receptor as a unique target for anti-glioblastoma therapy
S R Husain1, B H Joshi, R K Puri
1Laboratory 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.
Abstract:
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.
Insights
A novel interleukin-13 (IL-13) toxin effectively targets glioblastoma cells expressing IL-13 receptors. This therapy demonstrated complete tumor regression in mice, paving the way for clinical trials in recurrent glioblastoma patients.
Area of Science:
- Oncology
- Molecular Biology
- Drug Development
Background:
- Glioblastoma survival rates remain poor despite conventional treatments like surgery, radiotherapy, and chemotherapy.
- Targeting specific cellular receptors offers a promising avenue for novel glioblastoma therapies.
Purpose of the Study:
- To investigate the efficacy of an interleukin-13 (IL-13) cytotoxin in targeting and eliminating glioblastoma cells.
- To evaluate the therapeutic potential of IL-13 toxin (IL13-PE38QQR) in preclinical glioblastoma models.
Main Methods:
- Utilized a chimeric IL-13 toxin (IL13-PE38QQR) targeting IL-13 receptors on human glioblastoma cell lines.
- Administered IL-13 toxin via intratumoral, intraperitoneal, and intravenous routes in mouse models with human glioblastoma xenografts (U251 and U87).
- Assessed tumor regression, complete response rates, and duration of response following various dosing schedules.
Main Results:
- IL-13 toxin effectively killed a wide array of human glioblastoma cell lines expressing IL-13 receptors.
- Intratumoral injections led to complete and durable tumor regression in mouse models.
- Systemic administration (intraperitoneal and intravenous) showed significant tumor growth suppression and complete responses in a subset of mice.
- Therapy was well-tolerated with no visible signs of toxicity in treated animals.
Conclusions:
- The IL-13 toxin demonstrates potent anti-tumor activity against glioblastoma in preclinical models.
- Targeting IL-13 receptors with IL-13 toxin represents a viable therapeutic strategy for glioblastoma.
- These findings support the initiation of a Phase I clinical trial for recurrent glioblastoma.