Diao Dingwei, Zhai Jianxue, Yang Jianjun, Wu Hua, Jiang Jianjun, Dong Xiaoying, Passaro Antonio, Aramini Beatrice, Rao Shuan, Cai Kaican
Department of Thoracic Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Division of Thoracic Oncology, European Institute of Oncology, Milan, Italy.
Transl Lung Cancer Res. 2021 Feb;10(2):926-935. doi: 10.21037/tlcr-21-144.
Combining different cancer treatments represents a promising strategy to improve the therapeutic outcome for lung cancer patients with or without druggable gene alterations.
We previously developed a polyethylene glycol-based (PEG-based) immunostimulatory nanocarrier (PEG-Fmoc-NLG919) which can efficiently co-deliver an indoleamine 2,3-dioxygenase-1 (IDO1) inhibitor and the chemotherapeutic agent, paclitaxel. This method was found to improve cancer therapy by simultaneously performing immuno- and chemo-therapy. However, whether this nanocarrier could deliver targeted drugs to implement targeted therapy together with immunotherapy remains unclear.
Here, we report that the delivery of the classical tyrosine kinase inhibitor (TKI), gefitinib, with the optimized PEG-Fmoc-NLG919 nanocarrier, increased the sensitivity of lung cancer cells to gefitinib . Gefitinib was gradually but sufficiently released from the nanocarrier with comparable capacity to inhibit epidermal growth factor receptor (EGFR) activity as using free gefitinib directly. More importantly, treatment with gefitinib-loaded PEG-Fmoc-NLG919 could suppress lung tumor development more efficiently than gefitinib alone by inducing an immune active microenvironment with more functional CD8 T cells and less regulatory T cell infiltration.
Our study therefore demonstrates that delivery of small molecular targeted drugs with the immunostimulatory nanocarrier is a straightforward strategy for improving antitumor response for lung cancer therapy.
联合使用不同的癌症治疗方法是一种很有前景的策略，可改善有或没有可靶向治疗基因改变的肺癌患者的治疗效果。
我们之前开发了一种基于聚乙二醇（PEG）的免疫刺激纳米载体（PEG-Fmoc-NLG919），它可以有效地共同递送吲哚胺2,3-双加氧酶-1（IDO1）抑制剂和化疗药物紫杉醇。结果发现这种方法通过同时进行免疫治疗和化疗来改善癌症治疗。然而，这种纳米载体是否能够递送靶向药物以与免疫治疗一起实施靶向治疗仍不清楚。
在此，我们报告称，使用优化后的PEG-Fmoc-NLG919纳米载体递送经典酪氨酸激酶抑制剂（TKI）吉非替尼，可提高肺癌细胞对吉非替尼的敏感性。吉非替尼从纳米载体中逐渐但充分释放，其抑制表皮生长因子受体（EGFR）活性的能力与直接使用游离吉非替尼相当。更重要的是，用负载吉非替尼的PEG-Fmoc-NLG919进行治疗比单独使用吉非替尼能更有效地抑制肺肿瘤发展，因为它能诱导具有更多功能性CD8 T细胞和更少调节性T细胞浸润的免疫活性微环境。
因此，我们的研究表明，用免疫刺激纳米载体递送小分子靶向药物是提高肺癌治疗抗肿瘤反应的一种直接策略。
