Abstract A67: Reconditioning the tumor immune microenvironment for a breast cancer vaccine therapy.

Abstract

Abstract The recent approval of a prostate cancer vaccine has re-energized the research on cancer immunotherapy. A critical barrier for immunotherapies remains the immunosuppressive tumor microenvironment, which is due to abnormal tumor vasculature, hypoxia and tumor-infiltrating myeloid suppressors. Judiciously used anti-angiogenic agents have the potential to modulate the tumor immune environment to improve immunotherapy, but they are often used at high doses in the clinic aiming to prune tumor vessels. However, this has been shown to compromise other concurrent therapies, e.g., chemotherapy. Here, we demonstrate that anti-vascular endothelial growth factor receptor 2 (VEGFR2) antibody treatment at lower “vascular normalizing” doses – but not high “anti-vascular” doses – results in a more homogeneous distribution of functional tumor vessels and reduces hypoxia. As a result, the 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. These findings indicate that vascular normalizing doses of anti-VEGFR2 antibody treatment can reprogram the tumor immune microenvironment from suppressive to stimulatory. Based on this mechanism, synchronizing vascular normalization 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. 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 anti-angiogenic agents with active immunotherapy and potentially other anti-cancer therapies in a clinical setting. Citation Format: Yuhui Huang, Jianping Yuan, Elda Righi, Dan G. Duda, Dai Fukumura, Mark C. Poznansky, Rakesh K. Jain. Reconditioning the tumor immune microenvironment for a breast cancer vaccine therapy. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr A67.