Abstract 6190: Anti-tumor effects of lenvatinib plus anti-PD-1 in syngeneic murine cervical cancer models
Authors: Park Su-Bin , Kang Ji-Sik , Kim Min-Je , Lee Shin-Wha , Kang Dong-Woo , Kim Yong-Man 
Published: June 2022

Abstract
Immune checkpoint inhibitors (ICIs) have been applied in patients with various solid tumors since they were approved by U.S. FDA in 2011. However, only less than 20% of patients benefit from ICIs including anti-programmed cell death protein 1 (aPD-1). Recently, many studies to improve the response of ICIs are in progress, and especially, vascular endothelial growth factor receptors (VEGFR) pathway was emerged as major target. VEGFR inhibitors regulate the differentiation of tumor-associated macrophage, antigen presenting dendritic cell, and T cell infiltration, so they make a synergic antitumor effect with ICIs. In this study, we investigated the effect of lenvatinib combined with anti-mouse PD-1 in syngeneic murine cervical cancer models to show whether VEGFRi enhance the antitumor effect of ICIs. We established syngeneic mouse models of cervical cancer to confirm synergic effect by lenvatinib combined with aPD-1. 1x107 cells of U14 cells were injected subcutaneously into the flanks of BALB/c wild- type (immunocompetent) mice and BALB/c nude (immunocompromised) mice. They were treated with lenvatinib when the tumor volume reached at 200 mm3, subsequently, aPD-1 was administered in immunocompetent mice. We administrated lenvatinib (10 mg/kg, orally, daily) and aPD-1(200 µg per mouse, intraperitoneally (I.P), twice a week) for 3 weeks. Tumor volume was measured twice a week. After the end of the experiment, we harvested tumors and spleens, and performed histological analysis. All experiments were approved by the Institutional Animal Use and Care Committee (IACUC) in Asan Institute for Life Science.Although the tumor was increased despite lenvatinib treatment in immunocompromised model with BALB/c nude mice, on the 17th day after injection, the tumor growth was inhibited in lenvatinib group compared with vehicle group (2914 mm3 vs. 3663 mm3, respectively) (P=0.0014). On the other hand, the tumor volume was significantly reduced by lenvatinib in the immunocompetent model (278 mm3 in Len vs. 490 mm3 in Veh) (P=0.0347), particularly the tumor size was decreased since 2 weeks of injection. Subsequently, we investigated the synergistic effects of combination with lenvatinib and aPD-1 in immunocompetent model. Each single treatment group showed the reduction of tumor volume compared to vehicle group (278 mm3 in Len and 258 mm3 in aPD-1 vs. 490 mm3 in Veh). Furthermore, the lenvatinib plus aPD-1 combination group reduced tumor volume to 110mm3 on the 24th day after injection and it was significantly different compared to each single treatment group (P=0.13868 and P=0.27385, respectively).In this study, anti-tumor effect of aPD-1 was enhanced by the regulation of tumor microenvironment with lenvatinib in immunocompetent murine cervical cancer models. In conclusion, addition of lenvatinib is expected to increase the efficacy of ICIs in patients with cervical cancer who have the resistance or insensitivity to ICIs.
Citation Format: Su-Bin Park, Ji-Sik Kang, Min-Je Kim, Shin-Wha Lee, Dong-Woo Kang, Yong-Man Kim. Anti-tumor effects of lenvatinib plus anti-PD-1 in syngeneic murine cervical cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6190.