Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment.
Development of a nanoparticle-based immunotherapy targeting PD-L1 and PLK1 for lung cancer treatment.
复制标题
DOI：
10.1038/s41467-022-31926-9
复制
发表时间：
2022-07-23
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
作者：
靶向PD-L1和PD-1的免疫检查点抑制剂（ICIs）改善了晚期非小细胞肺癌（NSCLC）患者的生存率。然而，只有少数NSCLC患者对ICIs有反应，这突出了需要更好的免疫治疗。在此，我们报道了一种基于纳米颗粒的免疫疗法，称为ARAC（抗原释放剂和检查点抑制剂），旨在提高PD-L1抑制剂的疗效。ARAC是一种纳米颗粒共递送PLK1抑制剂（volasertib）和PD-L1抗体。PLK1是一种关键的有丝分裂激酶，在包括NSCLC在内的各种癌症中过表达，并驱动癌症生长。抑制PLK1选择性地杀死癌细胞并上调存活癌细胞中的PD-L1表达，从而为ARAC以前馈方式靶向递送提供机会。在转移性肺肿瘤模型（LLC-JSP）中，ARAC使volasertib和PD-L1抗体的有效剂量降低了5倍，其作用主要由CD8+ T细胞介导。ARAC在另一种肺肿瘤模型（KLN-205）中也显示出疗效，该模型对CTLA-4和PD-1抑制剂联合使用无反应。这项研究强调了一种合理的组合策略，通过利用我们的纳米颗粒平台来增强现有的治疗方法，该平台可以一次装载多种货物类型。只有少数非小细胞肺癌（NSCLC）患者对免疫检查点抑制剂有反应。在这里，作者设计了一种纳米系统，用于共同递送PLK1抑制剂和PD-L1抗体，在临床前肺癌模型中显示出抗肿瘤免疫反应。
Immune checkpoint inhibitors (ICIs) targeting PD-L1 and PD-1 have improved survival in a subset of patients with advanced non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients respond to ICIs, highlighting the need for superior immunotherapy. Herein, we report on a nanoparticle-based immunotherapy termed ARAC (Antigen Release Agent and Checkpoint Inhibitor) designed to enhance the efficacy of PD-L1 inhibitor. ARAC is a nanoparticle co-delivering PLK1 inhibitor (volasertib) and PD-L1 antibody. PLK1 is a key mitotic kinase that is overexpressed in various cancers including NSCLC and drives cancer growth. Inhibition of PLK1 selectively kills cancer cells and upregulates PD-L1 expression in surviving cancer cells thereby providing opportunity for ARAC targeted delivery in a feedforward manner. ARAC reduces effective doses of volasertib and PD-L1 antibody by 5-fold in a metastatic lung tumor model (LLC-JSP) and the effect is mainly mediated by CD8+ T cells. ARAC also shows efficacy in another lung tumor model (KLN-205), which does not respond to CTLA-4 and PD-1 inhibitor combination. This study highlights a rational combination strategy to augment existing therapies by utilizing our nanoparticle platform that can load multiple cargo types at once. Only a minority of patients with non-small cell lung cancer (NSCLC) respond to immune checkpoint inhibitors. Here the authors design a nanosystem for the co-delivery of a PLK1 inhibitor and PD-L1 antibody, showing anti-tumor immune responses in preclinical lung cancer models.
登录
查看更多内容
影响因子：
5.7
作者：
Morry J;Ngamcherdtrakul W;Gu S;Reda M;Castro DJ;Sangvanich T;Gray JW;Yantasee W
通讯作者：
Yantasee W
影响因子：
5.7
作者：
Gutteridge RE;Ndiaye MA;Liu X;Ahmad N
通讯作者：
Ahmad N
影响因子：
12.4
作者：
Kempen PJ;Greasley S;Parker KA;Campbell JL;Chang HY;Jones JR;Sinclair R;Gambhir SS;Jokerst JV
通讯作者：
Jokerst JV
DOI：
10.1158/1078-0432.ccr-16-3215
发表时间：
2017-07-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jiao S;Xia W;Yamaguchi H;Wei Y;Chen MK;Hsu JM;Hsu JL;Yu WH;Du Y;Lee HH;Li CW;Chou CK;Lim SO;Chang SS;Litton J;Arun B;Hortobagyi GN;Hung MC
通讯作者：
Hung MC
影响因子：
--
作者：
Li, Mengyuan;Liu, Zhixian;Wang, Xiaosheng
通讯作者：
Wang, Xiaosheng