mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice
mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice
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DOI：
10.1073/pnas.1810002115
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发表时间：
2018-09-25
影响因子：
11.1
通讯作者：
Levy, Ronald
中科院分区：
文献类型：
--
作者：
Haabeth, Ole A. W.;Blake, Timothy R.;Levy, Ronald
体内递送编码抗原的mRNA是个性化癌症治疗的有前途的方法。mRNA疫苗的治疗功效取决于安全和有效的基因递送、mRNA的生物稳定性和疫苗的免疫学特性。在这里，我们描述了一个通用的和高效的mRNA疫苗递送系统，采用电荷改变可释放转运蛋白（CART）提供抗原编码的mRNA的抗原呈递细胞（APC）的发展和评价。我们在人外周血单核细胞中证明，CART疫苗可以激活针对mRNA编码的病毒表位的强大的抗原特异性免疫应答。在建立的小鼠模型中，我们证明CART在静脉注射后优先靶向次级淋巴器官中的专职APC，在皮下注射后靶向局部APC。注射最后，我们证明了与mRNA和Toll样受体配体共同配制的CART同时抑制和激活靶细胞，以产生免疫应答，可以治疗和治愈患有大型肿瘤的小鼠。
In vivo delivery of antigen-encoding mRNA is a promising approach to personalized cancer treatment. The therapeutic efficacy of mRNA vaccines is contingent on safe and efficient gene delivery, biological stability of the mRNA, and the immunological properties of the vaccine. Here we describe the development and evaluation of a versatile and highly efficient mRNA vaccine-delivery system that employs charge-altering releasable transporters (CARTs) to deliver antigen-coding mRNA to antigen-presenting cells (APCs). We demonstrate in human peripheral blood mononuclear cells that CART vaccines can activate a robust antigen-specific immune response against mRNA-encoded viral epitopes. In an established mouse model, we demonstrate that CARTs preferentially target professional APCs in secondary lymphoid organs upon i.v. injections and target local APCs upon s.c. injection. Finally, we show that CARTs coformulated with mRNA and a Toll-like receptor ligand simultaneously transfect and activate target cells to generate an immune response that can treat and cure mice with large, established tumors.