Human neurological cancer cells express interleukin‐4 (IL‐4) receptors which are targets for the toxic effects of IL4‐pseudomonas exotoxin chimeric protein

Abstract

Glioblastoma, glioma or neuroblastoma cells were examined for the expression of IL-4 receptors (IL-4R) by flow cytometric analysis and 125I-IL-4 binding. These cancer cell lines expressed IL-4R which were of high affinity (KD = 700 x 10(-12) M) on glioblastoma cells. To investigate the function of these receptors and to target potent cytotoxic antitumor agents to human neurological cancers, we utilized IL4-PE4E, which is composed of IL-4 and mutant Pseudomonas exotoxin (IL4-PE4E). This chimeric molecule was cytotoxic toward human glioblastoma, neuroblastoma and glioma tumor cells in a dose-dependent manner. The cytotoxicity of IL4-PE4E was specific, since it was neutralized by excess IL-4, and by an anti-IL-4 monoclonal antibody in all types of brain tumor tested. IL2-PE4E and IL6-PE4E were not cytotoxic, nor was an IL4-PE4E mutant lacking ADP-ribosylating activity, indicating the IL4-PE4E-mediated cytotoxicity of the brain tumor cells required both IL-4R binding and enzymatic toxin activity. These data indicate that human neurological cancer cells express IL-4R which are targets for the cytotoxic effects of IL4-toxin. In addition, our data also suggest that IL4-PE4E should be studied further as a potential treatment for human neurological cancers.

IL-4 receptors on human medulloblastoma tumours serve as a sensitive target for a circular permuted IL-4-Pseudomonas exotoxin fusion protein

“…In addition, in our recent study, we have found that cpIL4-PE is not cytotoxic or modestly cytotoxic to a neuronal cell line and NHA cell culture compared to 15 glioma primary cell cultures in which cpIL-4PE is highly cytotoxic (Joshi et al, unpublished results). Furthermore, it is known that resting B cells, monocytes, bone marrow cells and endothelial cells which express type I or type II IL-4 receptors are not sensitive to cpIL4-PE (Husain et al, 1997;Puri et al, 1994). These results suggest that there is a large therapeutic window in which one can target cpIL4-PE to cancer cells but cause little collateral damage to normal brain tissues or other immune and non-immune cells.…”

“…New active agents are needed to improve survival and enhance the quality of life of these patients. Our previous studies have identified abundant expression of receptors for IL-4 (IL-4R) on human brain tumour cells (Husain et al, 1998;Joshi et al, 2000;Puri et al, 1994Puri et al, , 1996a. Based on our preclinical efficacy and safety studies, we have begun a Phase I clinical trial, in which a recombinant chimeric protein composed of circularly permuted IL-4 fused with Pseudomonas exotoxin (cpIL4-PE or IL4(38-37)-PE38KDEL) is administered intratumouraly in patients with high-grade glioma (Rand et al, 2000).…”

Alternative activation of tumor-associated macrophages by IL-4

“…118,119 In addition, IL-4 may promote tumor growth by directly acting on tumor cells. Increased levels of IL-4R have been reported in a variety of human malignancies, [120][121][122][123][124][125] and IL-4 signaling in tumor cells has been shown to protect cells from apoptosis through upregulation of anti-apoptosis proteins including cFLIP, PED, Bcl-x L and Bcl-2.…”

Gene Therapy for High-Grade Glioma

“…71) However, gene transfer of these immunomodulating cytokines has revealed promising results, including complete tumor regression, in several preclinical studies. 51,59,79,86) Several early phase trials are currently underway for this approach. IFN-b is a potential cytokine with multiple antitumor effects, including direct antiproliferative effects and indirect antitumor effects such as immunomodulation.…”