Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Hokkaido 060-0812, Japan.
Int J Pharm. 2022 Aug 25;624:122034. doi: 10.1016/j.ijpharm.2022.122034. Epub 2022 Jul 18.
Programmed cell death 1 (PD-1) blockade combination to other drugs have attracted the interest of scientists for treating tumors resistant to PD-1 blockade. In this study, the impact of the interval, order of administration, and number of cycles of immunotherapeutic combination of stimulator of interferon genes (STING) pathway agonist loaded lipid nanoparticle (STING-LNP) and PD-1 antibody for inducing the optimal combined antitumor activity against a melanoma lung metastasis is reported. One cycle had no effect, but two and three cycles resulted in a combinedantitumor effect. The interval between the administration was found to influence the induction of the combined effect. The second and third doses increased the gene expression of the NK cell activation marker, interferon γ (IFN-γ), PD-1 and a ligand of PD-1 (PD-L1), whereas the first dose failed. NK cells in the lung showed an increase in the expression of the activation markers and PD-1 after the second dose. The combined antitumor effect of this combination therapy against melanoma lung metastasis model could be dependent on the interval as well as the number of doses of STING-LNP.These findings suggest the importance of the protocol setting when combining a nano system loaded with an immune adjuvant and PD-1 antibody.
程序性细胞死亡蛋白 1（PD-1）阻断联合其他药物治疗对 PD-1 阻断有耐药性的肿瘤引起了科学家的兴趣。在这项研究中，报告了干扰素基因刺激物（STING）通路激动剂负载脂质纳米颗粒（STING-LNP）和 PD-1 抗体免疫治疗联合的间隔、给药顺序和周期数对诱导针对黑色素瘤肺转移的最佳联合抗肿瘤活性的影响。一个周期没有效果，但两个和三个周期导致联合抗肿瘤作用。给药间隔被发现影响联合作用的诱导。第二和第三剂增加了 NK 细胞激活标志物、干扰素 γ（IFN-γ）、PD-1 和 PD-1 的配体（PD-L1）的基因表达，而第一剂则没有。第二剂后，肺中的 NK 细胞表达的激活标志物和 PD-1 增加。这种联合治疗对黑色素瘤肺转移模型的抗肿瘤作用可能依赖于 STING-LNP 的间隔以及剂量数。这些发现提示在联合使用负载免疫佐剂和 PD-1 抗体的纳米系统时，方案设置的重要性。
