Optimum combination of radiopharmaceuticals-based targeting-triggering-therapy effect and PD-L1 blockade immunotherapy
Optimum combination of radiopharmaceuticals-based targeting-triggering-therapy effect and PD-L1 blockade immunotherapy
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放射性药物靶向触发治疗效果与PD-L1阻断免疫治疗的最佳组合
DOI：
10.1002/adtp.202200193
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发表时间：
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影响因子：
4.6
通讯作者：
Zhide Guo
中科院分区：
文献类型：
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作者：
Xuejun Wen;Xinying Zeng;Changrong Shi;Jia Liu;Yiren Zhang;Mengqi Shi;Jingchao Li;Haojun Chen;Rongqiang Zhuang;Xiaoyuan Chen;Xianzhong Zhang;Zhide Guo
177lu放射配体治疗与免疫检查点阻断（ICB）联合治疗越来越受到关注。本研究旨在探讨177Lu - DOTA - EB - cRGDfK （177Lu - DER）的免疫调节作用（靶向-触发-治疗），并通过靶向放射性核素治疗（TRT）和ICB联合优化治疗效果。流式细胞术、免疫荧光分析和RT - qPCR证实PD‐L1表达的变化。通过单光子发射计算机断层成像验证了CT26和MC38结直肠肿瘤模型中177lu‐DER的肿瘤摄取。进一步，仔细滴定放射性核素剂量和治疗计划以优化治疗方案，并探索TRT与ICB协同作用的机制。结果表明，177lu辐照后PD‐L1表达上调。9.25 MBq177Lu‐DER TRT联合200µg αPD‐L1免疫疗法可显著抑制肿瘤生长并防止肿瘤复发。研究还发现，4 - h间隔是给药和ICB治疗之间的有效时间窗口。综上所述，基于序次给药整合素αvβ3靶向放射配体和PD - L1免疫检查点阻断剂，实现了一种有前景的肿瘤免疫治疗方案，强调了放射治疗与ICB联合用于精确癌症治疗的潜力。
The therapeutic alliance of177Lu radioligand therapy and immune checkpoint blockade (ICB) has gained increasing attention. This study aims to investigate the immunomodulatory effect (targeting‐triggering‐therapy) of177Lu‐DOTA‐EB‐cRGDfK (177Lu‐DER) and to optimize the therapeutic efficacy by combining targeted radionuclide therapy (TRT) and ICB. Flow cytometry, immunofluorescence analysis, and RT‐qPCR are conducted to confirm the change of PD‐L1 expression. Tumor uptakes of177Lu‐DER in CT26 and MC38 colorectal tumor models are verified through single photon emission computed tomography imaging. Further, the radionuclide dose and the treatment schedule to optimize the therapeutic scheme are carefully titrated and the mechanism of the synergy between TRT and ICB is explored. The results demonstrate that PD‐L1 expression is upregulated after irradiation of177Lu. The combination of 9.25 MBq177Lu‐DER TRT with 200 µg αPD‐L1 immunotherapy significantly inhibits tumor growth and protects against tumor recurrence. It is also found that 4‐h interval is an effective time window between radioligand administration and ICB therapy. In conclusion, a promising scheme for tumor immunotherapy is realized based on the sequential administration of integrin αvβ3‐targeted radioligand and PD‐L1 immune checkpoint blocker, emphasizing the potential of combining radiotheranostics with ICB for precision cancer therapy.