Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy.
Nuclear imaging-guided PD-L1 blockade therapy increases effectiveness of cancer immunotherapy.
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核成像引导的 PD-L1 阻断疗法可提高癌症免疫疗法的有效性。
DOI：
10.1136/jitc-2020-001156
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发表时间：
2020-11
影响因子：
10.9
通讯作者：
Wang F
中科院分区：
文献类型：
--
作者：
Gao H;Wu Y;Shi J;Zhang X;Liu T;Hu B;Jia B;Wan Y;Liu Z;Wang F
提高程序性死亡-1(PD-1)/程序性死亡配体-1(PD-L1)检查点阻断治疗的反应性的策略仍然是癌症免疫治疗中的一个重要课题。本研究在99mTC-MY1523 SPECT/CT显像的指导下，研制了一种新型的针对PD-L1的放射性标记纳米体靶向显像剂99mTC-MY1523，用于提高PD-L1阻断免疫治疗的疗效。体外测定了纳米体MY1523的结合亲和力和特异性。用~(99m)Tc标记MY1523，并进行了体内分布和单光子发射CT(SPECT)/CT研究。以干扰素-γ(干扰素-γ)为干预手段，建立不同水平PD-L1表达的动物模型，研究99mTC-MY1523SPECT/CT在体内无创检测肿瘤PD-L1表达的能力。最后，在99mTC-MY1523 SPECT/CT引导下对MC-38、A20和4T1荷瘤小鼠进行PD-L1阻断免疫治疗，并检测肿瘤浸润T细胞。MY1523与PD-L1具有较高的结合亲和力和特异性，与治疗性抗体无竞争性结合。制备的99mTC-MY1523具有较高的比活度和放化纯度。99mTC-MY1523SPECT/CT显示，在MC-38、A20和4T1荷瘤小鼠模型中，干扰素-γ干预可动态上调肿瘤PD-L1的表达。在99mTC-MY1523 SPECT/CT显像确定的治疗时间窗内开始的PD-L1阻断治疗可显著提高所有动物模型的治疗效果，同时有效地抑制肿瘤生长，明显延长小鼠的存活时间。动态上调的PD-L1表达与PD-L1阻断治疗效果的改善相关，并证实了影像引导治疗后效应性T细胞对肿瘤的浸润显著增加。结果表明，99mTC-MY1523 SPECT/CT可实时、定量、动态地定位PD-L1在体内的表达，影像引导下的PD-L1阻断免疫治疗显著提高了治疗效果。这一策略值得转化为临床实践，以便更好地管理放疗或化疗的联合治疗。
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 99mTc-MY1523 targeting PD-L1 for the enhanced therapeutic efficacy of PD-L1 blockade immunotherapy by the guidance of 99mTc-MY1523 SPECT/CT imaging. The binding affinity and specificity of nanobody MY1523 were measured in vitro. MY1523 was radiolabeled with 99mTc 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 99mTc-MY1523 SPECT/CT for the in vivo non-invasive measurement of PD-L1 expression in tumors. Finally, the PD-L1 blockade immunotherapies guided by 99mTc-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. MY1523 exhibited a high binding affinity and specificity to PD-L1 and had no competitive binding with the therapeutic antibody. 99mTc-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 99mTc-MY1523 SPECT/CT. The PD-L1 blockade therapy initiated during the therapeutic time window determined by 99mTc-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. Our results demonstrated that 99mTc-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.
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PD-1和PD-L1抑制剂作为癌症免疫疗法的一种形式的开发：对注册试验和未来考虑的全面综述。
影响因子：
10.9
作者：
Gong J;Chehrazi-Raffle A;Reddi S;Salgia R
通讯作者：
Salgia R
PD-1和PD-L1检查点信号传导抑制癌症免疫疗法：机制，组合和临床结果。
影响因子：
5.6
作者：
Alsaab HO;Sau S;Alzhrani R;Tatiparti K;Bhise K;Kashaw SK;Iyer AK
通讯作者：
Iyer AK
影响因子：
12.4
作者：
Chakravarty R;Goel S;Cai W
通讯作者：
Cai W
影响因子：
7.3
作者：
Gibbons Johnson RM;Dong H
通讯作者：
Dong H
DOI：
10.1007/978-1-4939-8648-4_26
发表时间：
2018-01-01
期刊：
ANTIBODY ENGINEERING, 3 EDITION
影响因子：
--
作者：
Crauwels, Maxine;Massa, Sam;Muyldermans, Serge
通讯作者：
Muyldermans, Serge