用电荷改变可释放转运蛋白的mRNA接种引发人T细胞应答并治愈

StephenW

mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice
Ole A. W. Haabeth, Timothy R. Blake, Colin J. McKinlay, Robert M. Waymouth, Paul A. Wender, and Ronald Levy
PNAS September 25, 2018 115 (39) E9153-E9161; published ahead of print September 10, 2018 https://doi.org/10.1073/pnas.1810002115
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    Contributed by Ronald Levy, August 11, 2018 (sent for review June 21, 2018; reviewed by Mac Cheever and Paul M. Sondel)

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Significance

The RNA delivery field is mostly focused on lipid nanoparticles (LNPs). Although promising, LNPs have several limitations with respect to pharmacokinetics, biodistribution, and toxicity. The mechanism of RNA charge-altering releasable transporters (CART) delivery and release is unique. It proceeds dynamically with a controllable change in physical properties. Differing from all mRNA delivery systems, a key attribute of CARTs is a charge-altering degradation mechanism, which transforms the initial polycationic CART into neutral byproducts, thereby enabling endosomal escape, release, and subsequent translation of the polyanionic mRNA cargo. With this study, we introduce a potentially general approach to therapeutic vaccination enabled by a dynamic drug-delivery system (mRNA-CART) and demonstrate its utility in suppressing tumor formation and in eliminating established tumors.
Abstract

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.

    cancer vaccinationmRNAnanoparticlesT cell responsesimmunotherapy

StephenW

用电荷改变可释放转运蛋白的mRNA接种引发人T细胞应答并治愈小鼠中建立的肿瘤
Ole A. W. Haabeth，Timothy R. Blake，Colin J. McKinlay，Robert M. Waymouth，Paul A. Wender和Ronald Levy
PNAS 2018年9月25日115（39）E9153-E9161;发布于2018年9月10日之前的出版物https://doi.org/10.1073/pnas.1810002115
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    供稿人：Ronald Levy，2018年8月11日（发送于2018年6月21日审查;由Mac Cheever和Paul M. Sondel审阅）

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意义

RNA递送领域主要集中在脂质纳米颗粒（LNP）上。尽管有希望，但LNP在药代动力学，生物分布和毒性方面具有一些局限性。 RNA电荷改变可释放转运蛋白（CART）递送和释放的机制是独特的。它通过物理属性的可控变化动态地进行。与所有mRNA递送系统不同，CART的关键属性是电荷改变降解机制，其将初始聚阳离子CART转化为中性副产物，从而使得聚阴离子mRNA货物的内体逃逸，释放和随后的翻译成为可能。通过这项研究，我们引入了一种潜在的通用方法，通过动态药物传递系统（mRNA-CART）实现治疗性疫苗接种，并证明其在抑制肿瘤形成和消除既定肿瘤方面的效用。
抽象

编码抗原的mRNA的体内递送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，我们描述了多功能和高效mRNA疫苗递送系统的开发和评估，该系统使用电荷改变可释放转运蛋白（CART）将抗原编码mRNA递送至抗原呈递细胞（APC）。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。在已建立的小鼠模型中，我们证明了CART在i.v.时优先针对次级淋巴器官中的专业APC。在皮下注射并靶向局部APC注射。最后，我们显示与mRNA和Toll样受体配体共同配制的CART同时转染并激活靶细胞以产生免疫应答，该免疫应答可以治疗和治愈具有大的已确定肿瘤的小鼠。

    癌症疫苗接种mRNA纳米粒子T细胞应答免疫疗法

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