자궁 경부암 마우스 모델에서 렌바티닙과 항 PD-1의 항종양 효과에 대한 연구

Abstract

Background Immune checkpoint inhibitors (ICIs) have been used in patients with various solid tumors since they were approved by the U.S. FDA in 2011, but only less than 20% of them benefit from ICIs, including anti-programmed cell death protein 1 (anti-PD-1). Recently, many attempts to improve the response of ICIs are in progress. In particular, the vascular endothelial growth factor receptor (VEGFR) pathway has emerged as a major target, which has synergistic anti-tumor effects with ICIs by regulating the differentiation of tumor-associated macrophages, antigen-presenting dendritic cells, and T cell infiltration in VEGFRi. In this study, the effects of lenvatinib combined with anti-PD-1 were evaluated in a syngeneic murine model of uterine cervical cancer to demonstrate whether VEGFR inhibition enhances the anti-tumor effects of ICIs.

Materials and methods To evaluate the synergistic effects of lenvatinib and anti-PD-1, a synthetic mouse model of cervical cancer was used. A total of 1 107 U14 cells were injected subcutaneously into the flanks of BALB/c wild-type and nude mice. They were treated with lenvatinib (10 mg/kg, orally, daily) until the tumor volume reached 200 mm3, and then anti-PD-1 (200 µg per mouse, intraperitoneally (I.P.), twice a week) was administered to immunocompetent mice for 3 weeks. Tumor volume was measured twice a week. At the end of the experiment, tumors and spleens were harvested and histological analysis was performed.

Results Tumor volume was significantly reduced by lenvatinib in the immunocompetent model (278 mm3 in Len vs. 490 mm3 in Veh) (p = 0.0156); in particular, the tumor size decreased after 2 weeks of injection. In study, the synergistic effects of lenvatinib and anti-PD-1 were also confirmed in immune mouse models. Each single treatment group showed a reduction in tumor volume compared to the vehicle group (Len: 278 mm3; anti-PD-1: 258 mm3; Veh: 490 mm3). Furthermore, the lenvatinib plus anti-PD-1 group showed reduced tumor volume to 110 mm3 on the 24th day after injection, which was significantly different compared to each single treatment group (p = 0.0078 and p = 0.0078, respectively).

Conclusions In this study, the anti-tumor effects of anti-PD-1 were enhanced by the modulation of the tumor microenvironment with lenvatinib in immunocompetent murine cervical cancer models. In conclusion, the addition of lenvatinib is expected to increase the efficacy of ICIs in patients with cervical cancer who are resistant or insensitive to ICIs.