Cytokine receptor as a sensitizer for targeted cancer therapy.

Abstract

Introducing a cytokine receptor as a sensitizer into cancer cells offers a unique opportunity for receptor-targeted cancer therapy. It has been shown that transfection of the tumor necrosis factor (TNF) receptor gene in cancer cells or exposing cancer cells to certain reagents which increase expression of TNF receptors results in enhancement of the cytotoxic effect of TNF. In addition, the literature suggests that Fas/CD95-mediated apoptotic tumor cell killing is augmented by gene transfer of Fas into cancer cells or treatment of cells with agents like cisplatin and interferon (IFN)-gamma. In contrast to these approaches, we have discovered a new approach to cancer therapy; wherein introduction of a cytokine receptor chain into cancer cells sensitizes them to receptor-directed cytotoxins. We have demonstrated that when interleukin (IL)-13 receptor (IL-13R) alpha2 chain, one of the two known IL-13 binding proteins, is introduced into cancer cells that do not express this chain the cells acquire extreme sensitivity to a chimeric fusion cytotoxin composed of IL-13 and a mutated form of Pseudomonas exotoxin (IL13-PE). Cells that do not express this chain or express low levels show limited sensitivity to IL13-PE. Acquisition of sensitivity to IL13-PE was observed both in vitro and in vivo when IL-13R alpha2-transfected human tumor cells were implanted in immunodeficient animals followed by systemic or regional IL13-PE therapy. Our third generation experiments suggest that this approach is feasible for clinical situations as intratumor administration of plasmid carrying the IL-13R alpha2 chain gene sensitized these tumors to systemic or regional IL13-PE therapy. This unique approach comprising gene transfer of cytokine receptor chain and receptor-targeted cytotoxin administration represents a novel strategy for cancer therapy.