背景:Astatine-211是一种α发射器,具有高能α射线和对癌细胞的高细胞毒性。然而,靶向α治疗(TAT)也存在系统性免疫激活不足的问题,导致肿瘤转移和复发。联合免疫检查点阻断(ICB)与化学动力学疗法(CDT)可以增强抗肿瘤免疫力,这可能会放大TAT的免疫反应。本研究旨在通过三模型TAT-CDT-ICB策略阻止肿瘤转移和复发。
方法:我们成功设计了基于Mn的放射免疫疗法启动子(211At-ATE-MnO2-BSA),由211At组成,MnO2和牛血清白蛋白(BSA)。211At-ATE-MnO2-BSA在转移和复发模型中作为单一疗法或与抗PD-L1组合进行了研究。通过流式细胞术分析放射免疫疗法启动子对细胞毒性T淋巴细胞和树突状细胞(DC)的免疫作用。采用酶联免疫吸附法和免疫荧光法探讨其作用机制。
结果:这种放射免疫疗法启动子不仅可以增强TAT和CDT的治疗效果,而且还通过激活树突状细胞诱导强大的抗癌免疫活性。更有趣的是,当与免疫检查点抑制剂组合时,211At-ATE-MnO2-BSA可以有效地抑制原发性肿瘤和远端肿瘤的生长。
结论:三模型TAT-CDT-ICB策略提供了长期免疫记忆,消除原始肿瘤后可以防止肿瘤再攻击。因此,这项工作为TAT-CDT-ICB三模态癌症治疗提供了一种新的方法,在临床上抑制了转移和复发。
BACKGROUND: Astatine-211 is an α-emitter with high-energy α-ray and high cytotoxicity for cancer cells. However, the targeted alpha therapy (TAT) also suffers from insufficient systematic immune activation, resulting in tumor metastasis and relapse. Combined immune checkpoint blockade (ICB) with chemodynamic therapy (CDT) could boost antitumor immunity, which may magnify the immune responses of TAT. This study aims to discourage tumor metastasis and relapse by tri-model TAT-CDT-ICB strategy.
METHODS: We successfully designed Mn-based radioimmunotherapy promoters (211At-ATE-MnO2-BSA), which are consisting of 211At, MnO2 and bovine serum albumin (BSA). The efficacy of 211At-ATE-MnO2-BSA was studied as monotherapy or in combination with anti-PD-L1 in both metastatic and relapse models. The immune effects of radioimmunotherapy promoters on cytotoxic T lymphocytes and dendritic cells (DCs) were analyzed by flow cytometry. Enzyme-linked immunosorbent assay and immunofluorescence were used to explore the underlying mechanism.
RESULTS: Such radioimmunotherapy promoters could not only enhance the therapeutic outcomes of TAT and CDT, but also induce robust anti-cancer immune activity by activating dendritic cells. More intriguingly, 211At-ATE-MnO2-BSA could effectively suppress the growths of primary tumors and distant tumors when combined with immune checkpoint inhibitors.
CONCLUSIONS: The tri-model TAT-CDT-ICB strategy provides a long-term immunological memory, which can protect against tumor rechallenge after eliminating original tumors. Therefore, this work presents a novel approach for TAT-CDT-ICB tri-modal cancer therapy with repressed metastasis and relapse in clinics.