Journal Article

Immunomodulatory activity of lenvatinib contributes to antitumor activity in the Hepa1‐6 hepatocellular carcinoma model

Hori, Yusaku, Funahashi, Yasuhiro, Kodama, Kotaro, Tabata, Kimiyo, Kimura, Takayuki, Yamada, Kazuhiko, Ichikawa, Kenji, Kato, Yu, Matsui, Junji, Takase, Kazuma, Ito, Junichi, Ozawa, Yoichi, Nomoto, Kenichi

2018

Overview

Angiogenesis inhibitors such as lenvatinib and sorafenib, and an immune checkpoint inhibitor (ICI), nivolumab, are used for anticancer therapies against advanced hepatocellular carcinoma (HCC). Combination treatments comprising angiogenesis inhibitors plus ICIs are promising options for improving clinical benefits in HCC patients, and clinical trials are ongoing. Here, we investigated the antitumor and immunomodulatory activities of lenvatinib (a multiple receptor tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 1‐3, fibroblast growth factor receptor 1‐4, platelet‐derived growth factor receptor α, KIT and RET) and the combined antitumor activity of lenvatinib plus anti‐programmed cell death 1 (PD‐1) antibody in the Hepa1‐6 mouse HCC syngeneic model. We found that the antitumor activities of lenvatinib and sorafenib were not different in immunodeficient mice, but lenvatinib showed more potent antitumor activity than sorafenib in immunocompetent mice. The antitumor activity of lenvatinib was greater in immunocompetent mice than in immunodeficient mice and was attenuated by CD8+ T cell depletion. Treatment with lenvatinib plus anti‐PD‐1 antibody resulted in more tumor regression and a higher response rate compared with either treatment alone in immunocompetent mice. Single‐cell RNA sequencing analysis demonstrated that treatment with lenvatinib with or without anti‐PD‐1 antibody decreased the proportion of monocytes and macrophages population and increased that of CD8+ T cell populations. These data suggest that lenvatinib has immunomodulatory activity that contributes to the antitumor activity of lenvatinib and enhances the antitumor activity in combination treatment with anti‐PD‐1 antibody. Combination treatment of lenvatinib plus anti‐PD‐1 antibody therefore warrants further investigation against advanced HCC. Lenvatinib is a multitargeted tyrosine kinase inhibitor that selectively inhibits VEGFR1‐3, FGFR1‐4, PDGFRα, RET and KIT. Here, we show that lenvatinib has immunomodulatory activity, which plays a role in the antitumor activity of single lenvatinib treatment, and enhances the antitumor activity of anti‐PD‐1 antibody in the combination treatment in the Hepa1‐6 mouse HCC syngeneic tumor model.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Angiogenesis inhibitors / Animals / Antineoplastic Agents - administration & dosage / Antineoplastic Agents - pharmacology / Antineoplastic Agents, Immunological - administration & dosage / Antineoplastic Agents, Immunological - pharmacology / Antitumor activity / anti‐PD‐1 antibody / Apoptosis / Cancer therapies / Carcinoma, Hepatocellular - drug therapy / Carcinoma, Hepatocellular - genetics / Carcinoma, Hepatocellular - immunology / CD8 antigen / CD8-Positive T-Lymphocytes - cytology / CD8-Positive T-Lymphocytes - drug effects / Cell death / Cell Line, Tumor / Cell Proliferation - drug effects / Cell Survival - drug effects / Clinical trials / Enzyme inhibitors / Fibroblast growth factor receptor 1 / Hepatocellular carcinoma / Immune checkpoint inhibitors / Immunocompetence / Immunodeficiency / Immunomodulation / immunomodulatory activity / Kinases / Laboratories / lenvatinib / Liver cancer / Liver Neoplasms - drug therapy / Liver Neoplasms - genetics / Liver Neoplasms - immunology / Lymphocytes / Lymphocytes T / Macrophages / Metastasis / Mice / Monoclonal antibodies / Monocytes / Mortality / Original / PD-1 protein / Phenylurea Compounds - administration & dosage / Phenylurea Compounds - pharmacology / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Protein-tyrosine kinase receptors / Quinolines - administration & dosage / Quinolines - pharmacology / Response rates / Ret protein / Ribonucleic acid / RNA / Sequence Analysis, RNA / Single-Cell Analysis / sorafenib / Sorafenib - administration & dosage / Sorafenib - pharmacology / Targeted cancer therapy / Thyroid cancer / Tumors / Vascular endothelial growth factor / Xenograft Model Antitumor Assays