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• W3104637431 endingPage "e001156" @default.
• W3104637431 startingPage "e001156" @default.
• W3104637431 abstract "Objectives Strategies to improve the responsiveness of programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) checkpoint blockade therapy remain an essential topic in cancer immunotherapy. In this study, we developed a new radiolabeled nanobody-based imaging probe 99m Tc-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of 99m Tc-MY1523 SPECT/CT imaging. Methods The binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with 99m Tc by a site-specific transpeptidation of Sortase-A, and the biodistribution and single photon emission CT (SPECT)/CT were performed in mice bearing different tumors. We used interferon-γ (IFN-γ) as an intervention means to establish animal models with different levels of PD-L1 expression, then investigated the ability of 99m Tc-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by 99m Tc-MY1523 SPECT/CT were carried out in MC-38, A20, and 4T1 tumor-bearing mouse models, followed by the testing of tumor infiltration T cells. Results MY1523 exhibited a high binding affinity and specificity to PD-L1 and had no competitive binding with the therapeutic antibody. 99m Tc-MY1523 was prepared with high specific activity and radiochemical purity. It was found that tumor PD-L1 expression was dynamically upregulated by IFN-γ intervention in MC-38, A20, and 4T1 tumor-bearing mouse models, as indicated by 99m Tc-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by 99m Tc-MY1523 SPECT/CT imaging significantly enhanced the therapeutic efficacy in all animal models, while the tumor growth was effectively suppressed, and the survival time of mice was evidently prolonged. A correlation between dynamically upregulated PD-L1 expression and improved PD-L1 blockade therapy effectiveness was revealed, and the markedly increased infiltration of effector T cells into tumors was verified after the imaging-guided therapy. Conclusion Our results demonstrated that 99m Tc-MY1523 SPECT/CT allowed a real-time, quantitative and dynamic mapping of PD-L1 expression in vivo, and the imaging-guided PD-L1 blockade immunotherapy significantly enhanced the therapeutic efficacy. This strategy merits translation into clinical practice for the better management of combination therapies with radiotherapy or chemotherapy." @default.
• W3104637431 created "2020-11-23" @default.
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• W3104637431 date "2020-11-01" @default.
• W3104637431 modified "2023-10-15" @default.
• W3104637431 title "Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy" @default.
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• W3104637431 doi "https://doi.org/10.1136/jitc-2020-001156" @default.
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