Abstract 1555: Epigenetic modulation enhances the therapeutic effect of anti-IL13 receptor β2 antibody in human mesothelioma xenografts

Abstract

Purpose: Interleukin-13 receptor β2 (IL13Rα2) is known as a cancer antigen and high expression of this receptor is found in various human cancers, such as glioma, renal cell carcinoma and prostate carcinoma. Immunotoxin or cytotoxin therapy for malignant glioma targeting IL13Rα2 has already been investigated in preclinical and clinical trials. Here, we have examined the constitutive surface expression and the epigenetic regulation of IL13Rα2 by human mesothelioma. We have also investigated the therapeutic effect of the DNA methylation inhibitor, 5-aza-2′-deoxycytidine (5-aza-dC), and anti-IL13Rα2 monoclonal antibody on mesothelioma xenografts. Experimental Design: Cell surface expression of IL13Rα2 by various lung carcinomas was analyzed using flow cytometry. Therapeutic effects of anti-IL13Rα2 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 IL13Rα2 on their surface and that it was up-regulated by treatment with 5-aza-dC. This augmented expression of IL13Rα2 resulted in growth inhibition of the mesothelioma cells when co-cultured with anti-IL13Rα2 and effector cells, such as splenocytes and peritoneal exudate cells. The growth inhibition of mesothelioma cells was mediated by interferon-α that was only detected in the supernatant when effector cells were exposed to 5-aza-dC-treated tumors in the presence of anti-IL13Rα2. Compared with the control or either regimen alone, in vivo administration of anti-IL13Rα2 in combination with 5-aza-dC significantly prolonged the survival of mice with mesothelioma xenografts. Conclusion: These observations indicate a promising role for IL13Rα2 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. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1555. doi:1538-7445.AM2012-1555