Development of a recombinant interleukin-4-Pseudomonas exotoxin for therapy of glioblastoma

About 12,000 Americans are diagnosed with malignant astrocytoma each year. Despite surgery, radiotherapy, and chemotherapy, the prognosis of these pat ients remains poor. Targeted toxins based on the identification of novel an tigens or receptors provide a promising new approach to treating cancer. We have identified one such cell surface protein in the form of interleukin ( IL)-4 receptors (IL-4R) on human malignant astrocytoma. Normal brain tissue s from frontal cortex and temporal lobe cortex do not express IL-4R. To tar get IL-4R, we generated a chimeric fusion protein composed of IL-4 and Pseu domonas exotoxin (IL4-PE). This toxin is highly cytotoxic to IL-4R-bearing human brain cancer cells. Preclinical toxicologic experiments were performe d in mice, rats, and guinea pigs to determine an maximum tolerated dose. In trathecal administration in cynomolgus monkeys produced high cerebrospinal fluid levels without any central nervous system or other abnormalities. Whe n IL4-PE was injected into the right frontal cortex of rats, localized necr osis was observed at 1,000 but not less than or equal to 100 mu g/ml doses. Intravenous administration of this biologic to monkeys produced reversible grade 3 or grade 4 elevations of hepatic enzymes in a dose-dependent manne r. These results indicate that localized administration can produce nontoxi c levels of IL4-PE that may have significant activity against astrocytoma. In vivo experiments with nude mice have demonstrated that IL4-PE has signif icant antitumor activity against human glioblastoma tumor model. Intratumor administration of IL4-PE has been initiated for the treatment of malignant astrocytoma in a phase I clinical trial.