Abstract 2412: Sorafenib can be effectively combined with GM-CSF secreting cellular immunotherapy in a mouse model of HER-2+ breast cancer

Abstract

Abstract Due to the complexities of the tumor microenvironment and the frequent emergence of drug resistance with treatment, it is increasingly evident that cancer therapy will have to hit multiple host and tumor targets simultaneously. We previously reported that DC101, an antiangiogenic monoclonal antibody specific for the vascular endothelial growth factor receptor-2 (VEGFR-2), can enhance tumor immunity by a T cell-dependent mechanism. Sorafenib, a small molecule that also disrupts angiogenesis, blocks signaling through multiple kinases that control tumor growth and progression. It has also been reported to inhibit both dendritic cell (DC) and T cell function. To further explore the intrinsic tumor- and host-based effects of sorafenib, we tested it against murine HER-2+ breast tumor cells (NT) in vitro, and in NT-tumor-bearing FVB/N (immune-competent) and neu-N (immune tolerant to HER-2) mice in vivo. Sorafenib inhibited the growth of NT tumor cells in vitro, inducing apoptosis. Western blot analysis revealed that Sorafenib interfered with ERK/MAPK, but not AKT, signaling pathways, both of which are constitutively activated when HER-2 is over-expressed. Single agent sorafenib effectively controlled the growth of established tumors in immune competent FVB/N mice, but did not result in complete tumor clearance. In contrast, sorafenib alone did not significantly impact the outgrowth of established tumors in neu-N mice, where tumor-specific immune tolerance is in play. Consistent with this observation, depletion studies conducted in immune competent FVB/N mice revealed that the control of tumor growth is in part dependent on T cells, but not macrophages or NK cells. While sorafenib treatment alone did not induce immunity specific for RNEU420–429 (the immunodominant HER-2 epitope), it did accelerate tumor clearance induced by vaccination with a granulocyte-macrophage colony-simulating factor (GM-CSF)-secreting, HER-2+ cellular vaccine in tumor-bearing FVB/N mice compared to either drug treatment or vaccination alone. Finally, sorafenib neither augmented nor inhibited the vaccine-induced T cell response specific for RNEU420–429 as measured by ELISPOT and intracellular cytokine staining. Overall, these findings suggest that vaccine-based immunotherapy can interact with kinase inhibitors by distinct mechanisms for enhanced therapeutic response. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2412.