, Volume 65, Issue 1, pp 15-25

Interleukin-4-Pseudomonas Exotoxin Chimeric Fusion Protein for Malignant Glioma Therapy

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Abstract

Human malignant glioma cell lines, primary cell cultures, and tumor specimens derived from surgical samples have been shown to overexpress high-affinity receptors (R) for interleukin-4 (IL-4) in vitro and in situ. The significance of IL-4R expression on malignant glioma cells is still unclear. However, IL-4 has been reported to mediate functional effects in several solid tumor cell lines. These activities include inhibition of cell proliferation, regulation of adhesion molecules, and induction of signal transduction through the JAK/STAT pathway. To target IL-4Rs on tumor cells, we have produced a chimeric recombinant fusion protein consisting of a binding ligand, circularly permuted IL-4 and a mutated form of Pseudomonas exotoxin. This molecule is termed IL4(38–37)-PE38KDEL, cpIL4-PE, or IL-4 cytotoxin. Recombinant cpIL4-PE is highly and specifically cytotoxic to glioma cell lines in vitro, while it is not cytotoxic or less cytotoxic to hematopoietic and normal brain cells. In a nude mouse model, cpIL4-PE showed significant antitumor activity and partial or complete regression of small or large established human glioblastoma tumors. Encouraging preclinical efficacy, safety, and tolerability studies lead to testing of this agent in patients with recurrent glioblastoma. Based on these pilot studies, an extended Phase I/II clinical trial is currently ongoing to determine safety, tolerability, and efficacy of cpIL4-PE when injected stereotactically directly into the recurrent glioma by convection enhanced delivery. Preliminary clinical results suggest that cpIL4-PE can cause pronounced necrosis of recurrent glioma tumors without systemic toxicity. The central nervous system toxicities observed were attributed to the volume of infusion and/or nonspecific toxicity. Ongoing clinical trials will reveal antitumor activities of IL-4 cytotoxin in recurrent malignant glioma.