Integrin αvβ3-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy
Integrin αvβ3-targeted radionuclide therapy combined with immune checkpoint blockade immunotherapy synergistically enhances anti-tumor efficacy
复制标题
整合素αvβ3靶向放射性核素治疗联合免疫检查点阻断免疫治疗可协同增强抗肿瘤疗效。
DOI：
10.7150/thno.39203
复制
发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Chen, Xiaoyuan
中科院分区：
文献类型：
--
作者：
Chen, Haojun;Zhao, Liang;Chen, Xiaoyuan
理论基础：放射治疗结合免疫治疗在临床前研究和正在进行的临床试验中都显示出有希望的结果。靶向放射性核素治疗(TRT)是放射治疗的一个分支，涉及使用放射性同位素、放射性标记分子或纳米颗粒将粒子辐射传递到癌细胞。在常规治疗不再有效的转移性疾病中，TRT是一种很有前途的方法。TRT的使用越来越多，这就提出了如何最好地将TRT与免疫疗法结合起来的问题。在这项研究中，我们提出了一种基于PD-L1的免疫治疗和基于多肽的TRT(177Lu为放射性核素)相结合的治疗方案。方法：在~(177)Lu放射治疗的同时或顺序给予抗PD-L1抗体(αPD-L1mAb)，以探讨放射性核素治疗后免疫治疗的最佳时机。结果：TRT可使T细胞表面PD-L1的表达显著增加，联合应用αPD-L1mAb可刺激CD8T细胞的浸润，提高局部肿瘤控制、总生存期和抗肿瘤再攻击能力。此外，我们的数据显示，这种联合治疗的时间窗口可能对结果至关重要。结论：TRT是治疗转移性肿瘤的一种有希望的治疗方法。临床翻译结果表明，同时阻断PD-1/PD-L1轴而不是顺序阻断PD-1/PD-L1轴与TRT相结合可以改善总体生存率和长期肿瘤控制。
Rationale: Radiotherapy combined with immunotherapy has revealed promising outcomes in both preclinical studies and ongoing clinical trials. Targeted radionuclide therapy (TRT) is a branch of radiotherapy concerned with the use of radioisotopes, radiolabeled molecules or nanoparticles that deliver particulate radiation to cancer cells. TRT is a promising approach in cases of metastatic disease where conventional treatments are no longer effective. The increasing use of TRT raises the question of how to best integrate TRT with immunotherapy. In this study, we proposed a novel therapeutic regimen that combined programmed death ligand 1 (PD-L1)-based immunotherapy with peptide-based TRT (177Lu as the radionuclide) in the murine colon cancer model. Methods: To explore the most appropriate timing of immunotherapy after radionuclide therapy, the anti-PD-L1 antibody (αPD-L1 mAb) was delivered in a concurrent or sequential manner when 177Lu TRT was given. Results: The results demonstrated that TRT led to an acute increase in PD-L1 expression on T cells, and TRT in combination with αPD-L1 mAb stimulated the infiltration of CD8+ T cells, which improved local tumor control, overall survival and protection against tumor rechallenge. Moreover, our data revealed that the time window for this combination therapy may be critical to outcome. Conclusions: This therapeutic combination may be a promising approach to treating metastatic tumors in which TRT can be used. Clinical translation of the result would suggest that concurrent rather than sequential blockade of the PD-1/PD-L1 axis combined with TRT improves overall survival and long-term tumor control.