The tyrosine kinase inhibitor nintedanib enhances the efficacy of ⁹⁰Y-labeled B5209B radioimmunotherapy targeting ROBO1 without increased toxicity in small-cell lung cancer xenograft mice

Background Small cell lung cancer (SCLC) has a poor prognosis, and Roundabout homolog 1 (ROBO1) is frequently expressed in SCLC. ROBO1-targeted radioimmunotherapy (RIT) previously showed tumor shrinkage, but regrowth with fibroblast infiltration was observed. The fibroblasts would support tumor survival by secreting growth factors and cytokines. Inhibition of fibroblasts offers a candidate strategy for increasing RIT efficacy. Here, we evaluated the efficacy of combination therapy with Y-90-labeled anti-ROBO1 antibody B5209B (Y-90-B5209B) and the tyrosine kinase inhibitor nintedanib in SCLC xenograft mice.Methods Subcutaneous NCI-H69 SCLC xenograft mice were divided into four groups: saline, nintedanib alone, RIT alone, and a combination of RIT with nintedanib (combination). A single dose of 7.4 MBq of Y-90-B5209B was injected intravenously. Nintedanib was orally administered at a dose of 400 mu g five times a week for 4 weeks. Tumor volumes and body weights were measured regularly. Tumor sections were stained with hematoxylin and eosin or Masson trichrome.Results All six tumors in the combination therapy group disappeared, and four tumors showed no regrowth. Although RIT alone induced similar tumor shrinkage, regrowth was observed. Prolonged survival in thecombination therapy group was found compared with the other groups. Temporary body weight loss was observed in RIT and combination therapy. There is no difference in fibroblast infiltration between RIT alone and the combination.Conclusion Nintedanib significantly enhanced the anti-tumor effects of RIT with the Y-90-B5209B without an increase in toxicity. These findings encourage further research into the potential clinical application of combining RIT with nintedanib. Nucl Med Commun 45: 68-76 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc.