Preclinical trial of the multi-targeted lenvatinib in combination with cellular immunotherapy for treatment of renal cell carcinoma

Abstract

Abstract. Lenvatinib is an oral, multi-targeted tyrosine kinase inhibitor of vascular endothelial growth factor receptors 1-3, fibroblast growth factor receptors 1-4, platelet-derived growth factor receptor β, RET and KIT. Cellular immunotherapy has the potential to be a highly targeted treatment, with low toxicity to normal tissues and a high capacity to eradicate tumor tissue. The present study assessed the safety, maximum tolerated dose (MTD) and preliminary antitumor activity of lenvatinib and cellular immunotherapy in a murine model of renal cell carcinoma (RCC). The present study used a therapeutic dose of 0.12 mg lenvatinib and/or 10 4 rat uterine cancer adenocarcinoma (RuCa)-sensitized lymphocytes administered once daily continuously in 7-day cycles. Tumor regression was observed in mice with RCC following treatment with lenvatinib and 10 4 RuCa-sensitized lymphocytes. MTD was established as once daily administration of 0.18 mg lenvatinib and 10 6 RuCa-sensitized lymphocytes. The most common treatment-related adverse effects observed were fatigue (40%), mucosal inflammation (30%), proteinuria, diarrhea, vomiting, hypertension and nausea (all 40%). Combination therapy using lenvatinib and cellular immunotherapy enhanced the antitumor effect induced by single treatments and prolonged the survival of mice with RCC compared with either of the single treatments. Treatment with lenvatinib (0.12 mg) combined with 10 4

<p>Lenvatinib, a molecule with versatile application: from preclinical evidence to future development in anti-cancer treatment</p>

“…In addition, regulatory T cells express VEGFR-2, and stimulation through VEGF-A is connected with PD-1 increase and inhibition of T cells 30. A preclinical study in renal cell carcinoma (RCC) demonstrated that cellular immunotherapy in association with lenvatinib significantly increases survival in murine models; 31 furthermore, the association of lenvatinib and pembrolizumab has shown efficacy in a phase I study, particularly in RCC and melanoma,32 with a high disease-control rate.…”