小细胞肺癌（SCLC）预后不佳，轮状酸受体同源物 1（ROBO1）在SCLC中频繁表达。先前研究显示，ROBO1靶向放射免疫治疗（RIT）可导致肿瘤收缩，但观察到纤维母细胞浸润引起的肿瘤复苏。纤维母细胞通过分泌生长因子和细胞因子来支持肿瘤生存。抑制纤维母细胞提供了提高RIT效果的候选策略。本研究评估了90Y标记的抗ROBO1抗体B5209B（90Y-B5209B）与酪氨酸激酶抑制剂尼顿尼布联合治疗对SCLC异种移植小鼠的疗效。将皮下的NCI-H69 SCLC异种移植小鼠分为四组：生理盐水组、单独使用尼顿尼布组、单独使用RIT组和RIT与尼顿尼布联合组（联合组）。静脉注射一剂量为7.4MBq的90Y-B5209B。尼顿尼布以每天400µg的剂量口服给药，一周五次，疗程为4周。定期测量肿瘤体积和体重。使用苏木精和伊红染色或马森三色组织切片。联合治疗组中的六个肿瘤全部消失，四个肿瘤没有再生长。尽管RIT单独使用引起了类似的肿瘤收缩，但观察到了再生长。与其他组相比，联合治疗组中的生存时间延长。RIT和联合治疗组中观察到了暂时的体重下降。RIT单独使用与联合治疗组之间纤维母细胞浸润没有差异。尼顿尼布显著增强了90Y-B5209B联合RIT的抗肿瘤效果，而毒性并未增加。这些结果鼓励进一步研究将RIT与尼顿尼布联合应用于临床的潜力。版权所有 © 2023 The Author(s). 由 Wolters Kluwer Health, Inc. 发布。

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 90Y-labeled anti-ROBO1 antibody B5209B (90Y-B5209B) and the tyrosine kinase inhibitor nintedanib in SCLC xenograft mice.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 90Y-B5209B was injected intravenously. Nintedanib was orally administered at a dose of 400 µg 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.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 the combination 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.Nintedanib significantly enhanced the anti-tumor effects of RIT with the 90Y-B5209B without an increase in toxicity. These findings encourage further research into the potential clinical application of combining RIT with nintedanib.Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.