Preclinical studies with IL-13PE38QQR for therapy of malignant glioma.

To develop novel therapeutic agents for the treatment of brain tumors, we have been investigating the expression of unique tumor-associated receptors or antigens on the tumor cell surface. About six years ago, we discovered that human solid tumor cell lines, including human malignant glioma, express high- to intermediate-affinity receptors (R) for a Th2 cell-derived cytokine, interleukin-13 (IL-13). Analysis of the subunit composition of IL-13R in primary explants of malignant glioma cells has demonstrated that IL-13R is composed of three different chains (IL-13R alpha 1, IL-13R alpha 2 and IL-4R alpha, also known as IL-13R alpha', alpha and IL-4R beta, respectively) and that IL-13R alpha 2 chain is overexpressed on these cells. Normal brain tissues express IL-13R alpha 1 and IL-4R alpha chains, but show only marginal expression of IL-13R alpha 2 chain. Thus IL-13R alpha 2 chain appears to be overexpressed on glioma cells and may serve as a novel tumor biomarker or a target for receptor-directed therapeutic agents for brain tumors. To target IL-13 receptors, we have produced a recombinant fusion protein composed of IL-13 and a mutated form of Pseudomonas exotoxin (PE). This cytotoxin, termed IL-13PE38QQR or IL-13 cytotoxin, is highly and specifically cytotoxic to a spectrum of human glioma cell lines. In preclinical models of human glioblastoma tumors growing subcutaneously in immunodeficient mice, IL-13 cytotoxin has been found to have remarkable antitumor activity. The data that emerged from these studies reveal that localized or systemic administration of IL-13 cytotoxin can produce nontoxic drug levels and that IL-13 cytotoxin is potently effective against established glioblastoma tumors. On the basis of these and other preclinical studies, we have begun a phase I clinical trial using IL-13PE38QQR for therapy of recurrent malignant glioma.