Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy
Open Access
- 1 January 2020
- journal article
- research article
- Published by BMJ in Journal for ImmunoTherapy of Cancer
- Vol. 8 (2), e001156
- https://doi.org/10.1136/jitc-2020-001156
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 Tc-99m-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of Tc-99m-MY1523 SPECT/CT imaging. Methods The binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with Tc-99m 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-gamma (IFN-gamma) as an intervention means to establish animal models with different levels of PD-L1 expression, then investigated the ability of Tc-99m-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by Tc-99m-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. Tc-99m-MY1523 was prepared with high specific activity and radiochemical purity. It was found that tumor PD-L1 expression was dynamically upregulated by IFN-gamma intervention in MC-38, A20, and 4T1 tumor-bearing mouse models, as indicated by Tc-99m-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by Tc-99m-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 Tc-99m-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.Funding Information
- National Key R&D Program of China (2017YFA0205600, 2018YFC1313300, 2018YFE0205300)
- National Natural Science Foundation of China (81630045, 81671747, 81873907, 81920108020, 81927802, 81971676)
- Natural Science Foundation of Beijing Municipality (JQ19026, L172007)
- Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020110)
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