Abstract LB-344: Vascular normalization as an emerging strategy to enhance cancer immunotherapy.

Abstract

Abstract The recent approval of a prostate cancer vaccine has renewed hope for anti-cancer immunotherapies. However, the immunosuppressive tumor microenvironment may limit the effectiveness of current immunotherapies. Antiangiogenic agents have the potential to modulate the tumor microenvironment and improve immunotherapy, but they are often used at high doses in the clinic to prune tumor vessels and may paradoxically compromise various therapies. Here, we demonstrate that targeting tumor vasculature with lower “vascular normalizing” doses, but not high “anti-vascular/anti-angiogenic” doses of an anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody results in a more homogeneous distribution of functional tumor vessels. Furthermore, lower doses are superior to the high doses at polarizing tumor-associated macrophages from immune inhibitory M2-like towards immune stimulatory M1-like phenotype, and in facilitating CD4+ and CD8+ T cell tumor infiltration. Based on this mechanism, scheduling lower dose anti-VEGFR2 therapy with T cell activation induced by a whole cancer cell vaccine therapy enhanced anti-cancer efficacy in a CD8+ T cell-dependent manner in both immune tolerant and immunogenic murine breast cancer models. These findings indicate that vascular normalizing lower doses of anti-VEGFR2 antibody can reprogram the tumor microenvironment away from immunosuppression toward potentiation of cancer vaccine therapies. Given that the combinations of high doses of bevacizumab with chemotherapy have not improved overall survival of breast cancer patients, our study suggests a new strategy to more effectively use antiangiogenic agents in breast cancer with active immunotherapy and potentially other anti-cancer therapies. Citation Format: Yuhui Huang, Jianping Yuan, Elda Righi, Dan G. Duda, Dai Fukumura, Mark C. Poznanasky, Rakesh K. Jain. Vascular normalization as an emerging strategy to enhance cancer immunotherapy. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-344. doi:10.1158/1538-7445.AM2013-LB-344 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.