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

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Abstract
Both ceritinib (CER) and PD‐1/PD‐L1 have brought significant breakthrough for 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. Besides, the antitumor effect of combined CER with PD‐L1 inhibitor in ALK‐rearranged NSCLC are 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 blotting, peripheral blood mononuclear cells (PBMC) co‐culture system, plasmid and transfection experiments. Then, a Ba/F3 (EML4‐ALK‐WT) xenograft mice model was utilized to further evaluate the synergistic anticancer effects of CER and PD‐L1 inhibitor in vivo. Co‐culture system of PBMC with H2228 cell promotes the expression of PD‐L1 and phospho‐ERK, and combination 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 tumor volumes of combination were significant smaller than that either CER or PD‐L1 treatment. Besides, the relative tumor growth inhibitions were 84.9%, 20.0% and 91.9% for CER, PD‐L1 inhibitor and CER plus PD‐L1 group, respectively. CER could synergize with PD‐1/PD‐L1 blockade to yield enhanced anti‐tumor responses along with favorable tolerability of adverse effects. CER and PD‐L1 inhibitor combined produced a synergistic antineoplastic efficacy in vitro and in vivo, which provide a key insight and proof of principle for evaluating CER plus PD‐L1 blockade as combination therapy in clinical therapeutic practice.
Funding Information
  • National Natural Science Foundation of China (81703611)

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