Assessments of optimal timing for combined therapy with axitinib and immune check point inhibitor in a mouse renal cell carcinoma model

Abstract

Abstract Background Recently, several types of systemic therapy using tyrosine kinase inhibitor (TKI) and immune checkpoint inhibitor (ICI) have been performed for advanced renal cell carcinoma (aRCC) patients; however, the optimal strategy of sequential treatment with these agents has not been well established. The objective of this study was to determine the optimal timing for the introduction of TKI and ICI using a mouse RCC, RenCa model. Materials and Methods The effects of combined treatment of TKI and/or ICI with axitinib, anti-mouse programmed death (PD)-1, or PD-ligand 1 (PD-L1) antibody on tumor growth and survival after subcutaneous and intravenous injection of RenCa cells, respectively, were compared according to three different treatment schedules: simultaneous administration, initial axitinib administration, and initial ICI administration. Infiltrating patterns of lymphocytes into tumors after combined treatments were evaluated by immunohistochemical staining. Results In both the patients with anti-PD-1 and anti-PD-L1 antibodies, significantly marked inhibitory effects on subcutaneous growth of tumors were observed in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to those in the control without treatment. Survival intervals of mice after intravenous injection of RenCa cells were significantly longer in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Furthermore, both CD8 + to CD3 + and CD8 + to CD11b + T-lymphocyte ratios in subcutaneous RenCa tumors were significantly higher in the simultaneous and initial ICI administration, but not the initial axitinib administration, compared to the control. Conclusions Favorable control against aRCC progression may be achieved by administering TKI and ICI simultaneously or ICI followed by TKI.