University of Florida Lillian S. Wells Department of Neurosurgery, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Gainesville, FL 32610, USA.
University of Florida, Department of Pediatrics, Division of Hematology-Oncology, Gainesville, FL 32610, USA.
Cell. 2024 May 9;187(10):2521-2535.e21. doi: 10.1016/j.cell.2024.04.003. Epub 2024 May 1.
Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create "onion-like" multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became "hot" within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
癌症免疫疗法仍然受到抗原性差和调节性肿瘤微环境（TME）的限制。在这里，我们创建了“洋葱样”多层层状 RNA 脂质体聚集体（LPAs），以大大增强肿瘤 mRNA 抗原的有效载荷包封和免疫原性。与目前依赖于将有效载荷包封到纳米颗粒核心以在免疫细胞中结合 Toll 样受体的 mRNA 疫苗设计不同，系统给予的 RNA-LPAs 在基质细胞中激活 RIG-I，引发大量细胞因子/趋化因子反应和树突状细胞/淋巴细胞迁移，引发癌症免疫原性，并介导对早期和晚期小鼠肿瘤模型的排斥。在患有晚期神经胶质瘤的客户拥有的犬科动物中，RNA-LPAs 提高了存活率并重新编程了 TME，在单次输注后的几天内就变成了“热点”。在首例人体试验中，RNA-LPAs 在胶质母细胞瘤患者中迅速引发细胞因子/趋化因子释放、免疫激活/迁移、组织证实的假性进展和胶质母细胞瘤特异性免疫反应。这些数据支持 RNA-LPAs 作为一种新技术，同时重新编程 TME，同时引发快速和持久的癌症免疫疗法。
