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

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 104rat 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 104RuCa-sensitized lymphocytes. MTD was established as once daily administration of 0.18 mg lenvatinib and 106RuCa-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 104 RuCa-sensitized lymphocytes was associated with manageable toxicity consistent with individual agents. Further evaluation of this combination therapy in mice with advanced RCC is required. In conclusion, cellular immunotherapy and oncolytic therapy for cancer may be improved by the synergistic effects of lenvatinib and sensitized lymphocytes. In the present study, the inherent antineoplastic and immune stimulatory properties of the two agents were enhanced when used in combination, which may provide a basis for clinical treatment of patients with RCC.