Abstract 5035: Blockade of VEGF with ziv-aflibercept (VEGF Trap) enhances anti-tumor efficacy of CTLA-4 blocking antibody in an Fc dependent manner
Authors: Burova Elena , Ioffe Ella , Taduriyasas Chandrika , Allbritton Omaira , Tyagi Gaurav , Oyejide Lekan , Rudge John , Lowy Israel , Thurston Gavin 
Published: May 2015

Abstract
VEGF-dependent angiogenesis is required for tumor progression. Ziv-aflibercept (VEGF Trap) is a VEGF inhibitor, which exhibits potent antitumor activity in preclinical models and was approved by the FDA in combination with FOLFIRI for patients with metastatic colorectal cancer (mCRC) who did not respond or progressed following an oxaliplatin-containing regimen. Recent data suggest that VEGF blockade may also modulate tumor immunity by promoting necrosis and inflammation, however the precise mechanism is not fully understood. CTLA-4 blockade promotes tumor immunity by, in part, reversing suppressive effects of CTLA-4 receptor on T cell activation, and exhibits synergistic effects with other immunomodulatory agents in both clinical and experimental settings. In this study, we examined the combination of ziv-aflibercept (at 10 mg/kg) and CTLA-4 blocking antibody (at 200 ug/mouse) administered five times within two weeks in two mouse colon carcinoma models (Colon26 and MC38). Prophylactic therapy with either single agent inhibited Colon26 tumor growth. Responses to ziv-aflibercept were associated with reduction of tumor vascularity, while those to α-CTLA-4 murine IgG2b antibody were associated with enrichment of tumor CD8, but not CD4, T cells as measured by flow cytometry. Combination therapy resulted in complete tumor regression and significantly improved survival (0%, 30% and 70% survival in ziv-aflibercept, α-CTLA-4 and combination groups respectively). Pathological evaluation of ziv-aflibercept treated tumors by histostaining revealed increased tumor necrosis, which became more severe in the combination group. α-CTLA-4 antibody did not promote definitive tumor necrosis, but resulted in increased immune cell infiltrate composed mainly of lymphocytes and macrophages. To address the role of the immunoglobulin constant region of α-CTLA-4 antibody, we compared the effect of murine IgG2a and IgG2b antibody versions with high and low effector function respectively. α-CTLA-4 IgG2a antibody was significantly more potent than IgG2b, resulting in eradication of established Colon26 tumors and partial growth inhibition of established MC38 tumors, whereas these established tumors were resistant to α-CTLA4 IgG2b therapy. Co-administration of ziv-aflibercept significantly improved α-CTLA4 IgG2a antibody efficacy against established MC38 tumors. These results suggest that combining immunotherapy and ziv-aflibercept may be beneficial for the treatment of established tumors in a clinical setting.
Citation Format: Elena Burova, Ella Ioffe, Chandrika Taduriyasas, Omaira Allbritton, Gaurav Tyagi, Lekan Oyejide, John Rudge, Israel Lowy, Gavin Thurston. Blockade of VEGF with ziv-aflibercept (VEGF Trap) enhances anti-tumor efficacy of CTLA-4 blocking antibody in an Fc dependent manner. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5035. doi:10.1158/1538-7445.AM2014-5035