Lenvatinib mesylate (lenvatinib) is an orally administrated multiple receptor tyrosine kinase inhibitor that selectively inhibits the kinase activities of VEGFR1-3, FGFR1-4, KIT, PDGF-Rα and RET, which are involved in tumor angiogenesis and proliferation of several cancer types such as thyroid cancer. In order to investigate whether lenvatinib has effects on immune cell population in tumors, we examined antitumor effects and immune modulating abilities of lenvatinib in syngeneic murine tumor models.
[Materials and methods]
We examined antitumor activity of lenvatinib against BNL 1ME A.7R.1 murine hepatocellular carcinoma cell line in syngeneic and immune-deficient mice model. Combination treatment with lenvatinib at 10mg/kg (qd) plus anti-PD-1 mAb at 500μg/ml (twice weekly) was conducted in LL/2 murine Lewis lung carcinoma cell line syngeneic model. For immune population analyses, lenvatinib at 10mg/kg was orally administrated in BNL 1ME A.7R.1 or LL/2 mice model. On Day 7 after starting treatment, percentages of immune populations were analyzed by flow cytometer. For cytokine analysis, IFNγ in CD8+ T cells was intracellularly stained and analyzed by flow cytometer. The expression of immune related molecules in tumors was analyzed by quantitative PCR.
Lenvatinib showed more potent inhibition of BNL 1ME A.7R.1 tumor growth in immune functional mice than in immune-deficient mice when given the same dose. A flow-cytometry analysis of immune populations in both BNL 1ME A.7R.1 and LL/2 tumors indicated that lenvatinib significantly decreased the percentage of tumor associated macrophages (TAM) with CD45+CD11b+Ly6GlowLy6ClowF4/80+ markers. In addition, immune inhibitory molecules were downregulated in tumors. Lenvatinib significantly increased the percentage of IFNγ-secreting CD8+ T cells in regional lymph node. In LL/2 tumor model, the combination effect of lenvatinib with anti-PD-1 mAb showed a superior antitumor activity to each monotherapy.
These results indicate that lenvatinib has more potent antitumor effect in immune functional environment. It was noteworthy that lenvatinib decreased TAM population in tumors. Furthermore, lenvatinib enhanced antitumor activity of PD-1 signal inhibitors with combination treatment.
Citation Format: Yu Kato, Kimiyo Tabata, Yusaku Hori, Sho Tachino, Kiyoshi Okamoto, Junji Matsui. Effects of lenvatinib on tumor-associated macrophages enhance antitumor activity of PD-1 signal inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A92.