Purpose

In order to maximize synergistic effect of targeted radionuclide therapy (TRT) and immune checkpoint blockade (ICB) as well as reduce the toxicity, we pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy.

Methods

As a novel targeted radiotherapeutic agent, ¹⁷⁷Lu-AB-3PRGD₂ targeting integrin α_vβ₃ was developed to achieve sustained antitumor effect by introducing an albumin binder (AB) into the structure of 3PRGD₂. The ¹⁷⁷Lu-AB-3PRGD₂ TRT as well as different types of combination therapies of ¹⁷⁷Lu-AB-3PRGD₂ TRT and anti-PD-L1 ICB were performed in animal models. The changes of PD-L1 expression in tumors after TRT were evaluated in vitro and in vivo by PD-L1-specific SPECT/CT imaging of ^99mTc-MY1523.

Results

¹⁷⁷Lu-AB-3PRGD₂ showed improved tumor uptake and prolonged tumor retention, leading to significantly enhanced tumor growth suppression. Moreover, ¹⁷⁷Lu-AB-3PRGD₂ TRT remodeled the tumor immune microenvironment by upregulating PD-L1 expression and increasing tumor-infiltrating CD8⁺ T cells, facilitating immunotherapy. We found that the anti-PD-L1 treatment was more effective during the upregulation of tumor PD-L1 expression, and the time window could be determined by ^99mTc-MY1523 SPECT/CT.

Conclusion

We developed a novel and long-acting radiotherapeutic agent ¹⁷⁷Lu-AB-3PRGD₂, and pioneered a strategy guided by PD-L1-targeted nuclear medicine imaging for the combination of TRT and ICB towards precision cancer therapy, optimizing the therapeutic efficacy and reducing the cost and potential toxicity risks. This strategy could also be adapted for clinical practice, combining conventional radiotherapy or chemotherapy with ICB to enhance therapeutic efficacy.

中文翻译：

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PD-L1 表达的核成像促进靶向放射性核素治疗和免疫检查点阻断的协同抗肿瘤疗效

 目的

为了最大限度地发挥靶向放射性核素治疗 （TRT） 和免疫检查点阻断 （ICB） 的协同效应并降低毒性，我们开创了一种以 PD-L1 靶向核医学成像为指导的策略，将 TRT 和 ICB 联合用于精准癌症治疗。

 方法

作为一种新型靶向放射治疗剂，¹⁷⁷Lu-AB-3PRGD₂ 靶向整合素 α_vβ₃ 被开发出来，通过在 3PRGD₂ 的结构中引入白蛋白结合剂 （AB） 来实现持续的抗肿瘤效果。在动物模型中进行了 ¹⁷⁷Lu-AB-3PRGD₂ TRT 以及 ¹⁷⁷Lu-AB-3PRGD₂ TRT 和抗 PD-L1 ICB 的不同类型的联合疗法。通过 ^99mTc-MY1523 的 PD-L1 特异性 SPECT/CT 成像在体外和体内评估 TRT 后肿瘤中 PD-L1 表达的变化。

 结果

¹⁷⁷ 元Lu-AB-3PRGD₂ 显示肿瘤摄取改善和肿瘤滞留延长，导致肿瘤生长抑制显着增强。此外，¹⁷⁷Lu-AB-3PRGD₂ TRT 通过上调 PD-L1 表达和增加肿瘤浸润 CD8⁺ T 细胞来重塑肿瘤免疫微环境，促进免疫治疗。我们发现抗 PD-L1 治疗在肿瘤 PD-L1 表达上调期间更有效，时间窗可以通过 ^99mTc-MY1523 SPECT/CT 确定。

 结论

我们开发了一种新型长效放射治疗剂 ¹⁷⁷Lu-AB-3PRGD₂，并开创了以 PD-L1 靶向核医学成像为指导的 TRT 和 ICB 联合治疗癌症的策略，优化治疗效果并降低成本和潜在毒性风险。这种策略也可以适用于临床实践，将常规放疗或化疗与 ICB 相结合，以提高治疗效果。