Abstract 2756: Synergistic tumor-suppressive effect of apatinib, a selective VEGFR-2 inhibitor, in combination with immunotherapy in a syngeneic murine lung cancer model
Authors: Kim Bumjin , McGinn Arlo N. , Park Cheol Hee , Kim Sung Chul 
Published: August 2018

Abstract
Anti-angiogenesis therapy is considered one of several promising combination strategies with immunotherapy. The potential for synergistic combination is based on more than just the disparate mechanisms of action of limiting new vessel formation and circumventing cancer immune evasion. Beyond limiting sprouting of new vessels, angiogenesis inhibition is known to normalize existing tumor vasculature and ameliorate the immune-suppressive tumor microenvironment. These effects respectively increase the number of tumor-infiltrating lymphocytes in the tumor milieu and allow these immune agents to kill cancer cells more efficiently. So far, a number of preclinical studies have supported the benefit of combining anti-angiogenesis therapy with immunotherapy. Monoclonal antibodies targeting VEGF and VEGFR-2, as well as multi-kinase small-molecule inhibitors targeting VEGFR have shown synergistic efficacy in various tumor models. Those studies also revealed that this combination limits tumor growth through increasing anti-tumoral T-cell populations (e.g. CD4+ and CD8+ T-cells) as well as decreasing immune-suppressive immune cell populations (e.g. Treg and MDSCs). Moreover, clinically, the combination treatments have reached phase III development for hepatocellular, renal cell, non-small cell lung carcinoma, and ovarian cancer patients. Apatinib is an orally-available, small-molecule tyrosine kinase inhibitor of VEGFR-2 with high selectivity and potency (IC50 = 1.0 nM) as well as a low toxicity profile proven in multiple clinical trials. Apatinib has been approved in China for third-line gastric cancer and many clinical trials have been conducted worldwide for multiple tumor types including an ongoing global phase III gastric cancer study. Herein, we present preclinical outcomes that apatinib synergistically suppressed tumor growth when combined with anti-PD-1 immunotherapy. In this study, a LL/2 murine lung carcinoma syngeneic mouse model was used to test the tumor growth inhibition (TGI) activities of single-agent apatinib and anti-muPD-1 treatment as well as a combination of both agents. Over a 20-day period, the anti-muPD-1 antibody was dosed as a single agent at 10 mg/kg IP, BIW and apatinib was tested as a single agent at 75, 150, and 300 mg/kg, PO, QD and again at the same concentration in combination with anti-muPD-1 at 10 mg/kg. Apatinib mono-treatment (300 mg/kg) and anti-muPD-1 mono-treatment showed only 22% and 37% of TGI, respectively; however, the 300 mg/kg apatinib + anti-muPD-1 group showed the highest and most significant TGI of 55% (p&lt;0.0001). Collectively, we determined that apatinib treatment played a synergistic role on suppressing tumor growth when combining with anti-PD-1 treatment, which is encouraging for upcoming clinical trials of apatinib in combination with anti-PD-1 therapies planned for early 2018.
Citation Format: Bumjin Kim, Arlo N. McGinn, Cheol Hee Park, Sung Chul Kim. Synergistic tumor-suppressive effect of apatinib, a selective VEGFR-2 inhibitor, in combination with immunotherapy in a syngeneic murine lung cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2756.