Abstract 1544: Combined oncolytic virotherapy and immunotherapy for malignant mesothelioma

Abstract

Abstract Introduction. Oncolytic viruses have therapeutic potential in cancer by selectively replicating within malignant cells and/or other cells in the tumor tissues, causing cell death. Vaccinia virus (VACV) with deletion of viral genes encoding for thymidine kinase and vaccinia growth factor and armed with a chemokine gene encoding CCL5 (vvDD-CCL5) has been previously shown to be safe and efficacious in a murine colon cancer model (Li J. et al., Mol Ther., 19: 650-7; 2011). Here we explored combination therapy with the use of this armed oncolytic virus and immunotherapy in a murine malignant mesothelioma model in syngeneic BALB/c mice. Methods. The viral replication and oncolysis was examined in murine AB12 mesothelioma cancer cells in vitro, and the combination of oncolytic virus, IL-2 and anti-CD25 and anti-CTLA4 antibodies, was investigated in vivo to treat a murine model of peritoneal malignant mesothelioma (PMM) derived from AB12 cells in BALB/c mice. Results. In vitro, vvCCL5 and its parental virus vvDD replicate well in AB12 cancer cells and lead to efficient cytotoxicity in these cancer cells. In vivo biodistribution analysis indicated that both viruses displayed highly tumor selective replication; however, vvDD-CCL5 replicated to a greater extent and displayed increased persistence in the tumor tissue. As a result, vvDD-CCL5 was more efficient than vvDD, working in a viral dose-dependent manner and leading to increased survival of tumor-bearing mice. Combination therapy of virus with antibodies against CD25 and CTLA4 and IL-2 was investigated. Clearly, this has been the best strategy to treat AB12 PMM, achieving the best long-term survival of mice. We are currently investigating its cellular and molecular mechanisms by this combination leading to tumor regression and long-term survival of mice. Conclusions: The chemokine gene-armed oncolytic virus (vvDD-CCL5) is effective in a PMM tumor model. The combination of this virus with an immunologic regimen of Treg depletion and IL-2 treatment has been demonstrated to be highly efficacious for PMM. Further understanding of its cellular and molecular mechanisms of this treatment strategy will facilitate the optimization of combined therapeutic regimens for PMM. 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 1544. doi:1538-7445.AM2012-1544