Wang Feihu, Xu Dongqing, Su Hao, Zhang Weijie, Sun Xuanrong, Monroe Maya K, Chakroun Rami W, Wang Zongyuan, Dai Wenbing, Oh Richard, Wang Han, Fan Qin, Wan Fengyi, Cui Honggang
Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21218, USA.
Institute for NanoBiotechnology (INBT), Johns Hopkins University, Baltimore, MD 21218, USA.
Sci Adv. 2020 Apr 29;6(18):eaaz8985. doi: 10.1126/sciadv.aaz8985. eCollection 2020 May.
Immune checkpoint blockers (ICBs) have shown great promise at harnessing immune system to combat cancer. However, only a fraction of patients can directly benefit from the anti-programmed cell death protein 1 (aPD1) therapy, and the treatment often leads to immune-related adverse effects. In this context, we developed a prodrug hydrogelator for local delivery of ICBs to boost the host's immune system against tumor. We found that this carrier-free therapeutic system can serve as a reservoir for extended tumoral release of camptothecin and aPD1 antibody, resulting in an immune-stimulating tumor microenvironment for boosted PD-1 blockade immune response. Our in vivo results revealed that this combination chemoimmunotherapy elicits robust and durable systemic anticancer immunity, inducing tumor regression and inhibiting tumor recurrence and metastasis. This work sheds important light into the use of small-molecule prodrugs as both chemotherapeutic and carrier to awaken and enhance antitumor immune system for improved ICBs therapy.
免疫检查点阻断剂（ICBs）在利用免疫系统对抗癌症方面显示出巨大潜力。然而，只有一小部分患者能直接从抗程序性细胞死亡蛋白1（aPD1）治疗中获益，且该治疗常常导致免疫相关的不良反应。在此背景下，我们开发了一种用于局部递送ICBs以增强宿主抗肿瘤免疫系统的前药水凝胶剂。我们发现这种无载体治疗系统可作为喜树碱和aPD1抗体在肿瘤中持续释放的储存库，从而形成免疫刺激的肿瘤微环境以增强PD-1阻断免疫反应。我们的体内研究结果表明，这种联合化学免疫疗法可引发强大且持久的全身抗癌免疫，诱导肿瘤消退并抑制肿瘤复发和转移。这项工作为利用小分子前药作为化疗药物和载体来激活并增强抗肿瘤免疫系统以改善ICBs治疗提供了重要启示。
