Epigenetic Modulation Enhances the Therapeutic Effect of Anti-IL-13Rα2 Antibody in Human Mesothelioma Xenografts

Purpose: The interleukin-13 receptor alpha 2 (IL-13R alpha 2) is expressed by a variety of human malignant cells. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL-13R alpha 2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-dC) and anti-IL-13R alpha 2 monoclonal antibody on mesothelioma xenografts. Experimental Design: Cell surface expression of IL-13R alpha 2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti-IL-13R alpha 2 and 5-aza-dC were investigated using antibody-dependent cellular cytotoxicity and proliferation assays and by monitoring the survival of mesothelioma-bearing mice. Results: We found that human malignant mesotheliomas expressed surface IL-13R alpha 2 on their surface and that it was upregulated by treatment with 5-aza-dC. This augmented expression of IL-13R alpha 2 resulted in growth inhibition of the mesothelioma cells when cocultured with anti-IL-13R alpha 2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by IFN-gamma that was only detected in the supernatant when effector cells were exposed to 5-aza-dC-treated tumors in the presence of anti-IL-13R alpha 2. Compared with the control or either regimen alone, in vivo administration of anti-IL-13R alpha 2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts. Conclusions: These observations indicate a promising role for IL-13R alpha 2 as a target for antibody treatment in malignant mesothelioma, and, in combination with epigenetic regulation by a DNA methylation inhibitor, suggest the potential for a novel strategy to enhance therapeutic potency. Clin Cancer Res; 17(9); 2819-29. (C)2011 AACR.