Skaggs Pharmaceutical Sciences Center, Department of Pharmacology & Toxicology, College of Pharmacy, The University of Arizona, Tucson, AZ, USA.
NCI-Designated University of Arizona Comprehensive Cancer Center, Tucson, AZ, USA.
Nat Nanotechnol. 2021 Oct;16(10):1130-1140. doi: 10.1038/s41565-021-00950-z. Epub 2021 Aug 12.
Despite the enormous therapeutic potential of immune checkpoint blockade (ICB), it benefits only a small subset of patients. Some chemotherapeutics can switch 'immune-cold' tumours to 'immune-hot' to synergize with ICB. However, safe and universal therapeutic platforms implementing such immune effects remain scarce. We demonstrate that sphingomyelin-derived camptothecin nanovesicles (camptothesomes) elicit potent granzyme-B- and perforin-mediated cytotoxic T lymphocyte (CTL) responses, potentiating PD-L1/PD-1 co-blockade to eradicate subcutaneous MC38 adenocarcinoma with developed memory immunity. In addition, camptothesomes improve the pharmacokinetics and lactone stability of camptothecin, avoid systemic toxicities, penetrate deeply into the tumour and outperform the antitumour efficacy of Onivyde. Camptothesome co-load the indoleamine 2,3-dioxygenase inhibitor indoximod into its interior using the lipid-bilayer-crossing capability of the immunogenic cell death inducer doxorubicin, eliminating clinically relevant advanced orthotopic CT26-Luc tumours and late-stage B16-F10-Luc2 melanoma, and achieving complete metastasis remission when combined with ICB and folate targeting. The sphingomyelin-derived nanotherapeutic platform and doxorubicin-enabled transmembrane transporting technology are generalizable to various therapeutics, paving the way for transformation of the cancer immunochemotherapy paradigm.
尽管免疫检查点阻断 (ICB) 具有巨大的治疗潜力，但它仅使一小部分患者受益。一些化疗药物可以将“免疫冷”肿瘤转变为“免疫热”肿瘤，与 ICB 协同作用。然而，安全且通用的治疗平台实施这种免疫效果仍然很少。我们证明，鞘磷脂衍生的喜树碱纳米囊泡（喜树素体）引发强烈的颗粒酶 B 和穿孔素介导的细胞毒性 T 淋巴细胞（CTL）反应，增强 PD-L1/PD-1 共阻断，以根除皮下 MC38 腺癌并产生记忆免疫。此外，喜树素体改善了喜树碱的药代动力学和内酯稳定性，避免了全身毒性，深入肿瘤并优于 Onivyde 的抗肿瘤功效。喜树素体使用免疫原性细胞死亡诱导剂阿霉素的脂质双层穿越能力将吲哚胺 2,3-双加氧酶抑制剂吲哚美辛共同装载到其内部，消除了临床上相关的晚期原位 CT26-Luc 肿瘤和晚期 B16-F10-Luc2 黑色素瘤，并在与 ICB 和叶酸靶向联合使用时实现完全转移缓解。这种源自鞘磷脂的纳米治疗平台和阿霉素介导的跨膜转运技术具有通用性，可以应用于各种治疗方法，为癌症免疫化疗范式的转变铺平道路。
