A review of studies on targeting interleukin 4 receptor for central nervous system malignancy

Despite advances in biomedical sciences, the prognosis of patients with brain tumors remains poor. Effective treatment is lacking for these central nervous system (CNS) cancers. Targeted immunotoxins are a new class of therapeutic approaches that have emerged for the treatment of human cancers. In this approach, tumor antigen or cell surface receptor is targeted by a chimeric fusion protein consisting of an antibody or a ligand and a suicidal gene or toxin to kill tumor cells. In that regard, receptors for interleukin (IL)-4 (IL-4R) have been identified to be overexpressed on a variety of human CNS tumor cell lines and tissue samples including meningioma. In various studies, high grade brain tumor specimens and malignant brain tumor cell lines have been shown to overexpress high-affinity IL-4R, while normal brain samples or cell lines expressed lower levels of these receptors. The structures of IL-4R on CNS tumors have been studied, which demonstrate that these cells express predominantly type II IL-4R. These receptors are functional as IL-4 can cause signal transduction, inhibit growth of some tumor cell lines and increase expression of major histocompatibility antigens and intracellular adhesion molecular-1 (ICAM-1) on some tumor cells lines. To target IL-4R, a chimeric fusion protein composed of IL-4 and truncated Pseudomonas exotoxin has been developed. This cytotoxin is highly cytotoxic to IL-4R positive tumors in vitro and has been reported to be highly effective in pre-clinical animal model of human brain cancer. Several Phase I/II clinical trials for treatment of IL-4R positive cancers have been completed. This review article will summarize pre-clinical and clinical development of IL-4PE cytotoxin.