In vitro and in vivo synergistic efficacy of ceritinib combined with programmed cell death ligand-1 inhibitor in anaplastic lymphoma kinase-rearranged non-small-cell lung cancer

Abstract

Both ceritinib (CER) and programmed cell death (PD)-1/PD ligand-1 (PD-L1) have brought significant breakthroughs for anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC). However, the overall clinical efficacy of either CER or PD-1/PD-L1 inhibitor monotherapy has been limited to a large extent. In addition, the antitumor effect of combined CER and PD-L1 inhibitor in ALK-rearranged NSCLC is not fully understood. In H2228 cells, we examined the tumor killing effect of CER plus PD-L1 inhibitor in vitro by quantitative RT-PCR, flow cytometry, ELISA, western blot analysis, PBMC coculture system, and plasmid and transfection experiments. A Ba/F3 (EML4-ALK-WT) xenograft mouse model was also utilized to further evaluate the synergistic anticancer effects of CER and PD-L1 inhibitor in vivo. The coculture system of PBMCs with H2228 cells promotes the expression of PD-L1 and phospho-ERK, and combined treatments facilitate lymphocyte proliferation and activation, inhibit PD-L1 expression, and enhance lymphocyte cytotoxicity and cell death. In the in vivo NSCLC xenograft model, the volumes of tumors treated with CER and PD-L1 inhibitor in combination were significantly smaller than those treated with CER or PD-L1 alone. The relative tumor growth inhibitions were 84.9%, 20.0%, and 91.9% for CER, PD-L1 inhibitor, and CER plus PD-L1 groups, respectively. Ceritinib could synergize with PD-1/PD-L1 blockade to yield enhanced antitumor responses along with favorable tolerability of adverse effects. Ceritinib and PD-L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provides a key insight and proof of principle for evaluating CER plus PD-L1 blockade as combination therapy in clinical therapeutic practice.