全身性的RNA递送至树突细胞利用的癌症免疫治疗抗病毒防御

StephenW

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Nature | Letter


日本語要約

Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy

    Lena M. Kranz,    Mustafa Diken,    Heinrich Haas,    Sebastian Kreiter,    Carmen Loquai,    Kerstin C. Reuter,    Martin Meng,    Daniel Fritz,    Fulvia Vascotto,    Hossam Hefesha,    Christian Grunwitz,    Mathias Vormehr,    Yves Hüsemann,    Abderraouf Selmi,    Andreas N. Kuhn,    Janina Buck,    Evelyna Derhovanessian,    Richard Rae,    Sebastian Attig,    Jan Diekmann,    Robert A. Jabulowsky,    Sandra Heesch,    Jessica Hassel,    Peter Langguth,    Stephan Grabbe    et al.

   
    534,
    396–401
    (16 June 2016)
    doi:10.1038/nature18300

Received
    28 December 2015
Accepted
    06 May 2016
Published online
    01 June 2016
Corrected online
    07 June 2016



Lymphoid organs, in which antigen presenting cells (APCs) are in close proximity to T cells, are the ideal microenvironment for efficient priming and amplification of T-cell responses1. However, the systemic delivery of vaccine antigens into dendritic cells (DCs) is hampered by various technical challenges. Here we show that DCs can be targeted precisely and effectively in vivo using intravenously administered RNA-lipoplexes (RNA-LPX) based on well-known lipid carriers by optimally adjusting net charge, without the need for functionalization of particles with molecular ligands. The LPX protects RNA from extracellular ribonucleases and mediates its efficient uptake and expression of the encoded antigen by DC populations and macrophages in various lymphoid compartments. RNA-LPX triggers interferon-α (IFNα) release by plasmacytoid DCs and macrophages. Consequently, DC maturation in situ and inflammatory immune mechanisms reminiscent of those in the early systemic phase of viral infection are activated2. We show that RNA-LPX encoding viral or mutant neo-antigens or endogenous self-antigens induce strong effector and memory T-cell responses, and mediate potent IFNα-dependent rejection of progressive tumours. A phase I dose-escalation trial testing RNA-LPX that encode shared tumour antigens is ongoing. In the first three melanoma patients treated at a low-dose level, IFNα and strong antigen-specific T-cell responses were induced, supporting the identified mode of action and potency. As any polypeptide-based antigen can be encoded as RNA3, 4, RNA-LPX represent a universally applicable vaccine class for systemic DC targeting and synchronized induction of both highly potent adaptive as well as type-I-IFN-mediated innate immune mechanisms for cancer immunotherapy.
Subject terms:

    Immunization
    Cancer immunotherapy
    RNA vaccines
    Vaccines
    Drug delivery

StephenW

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自然|信


日本语要约

全身性的RNA递送至树突细胞利用的癌症免疫治疗抗病毒防御

    莉娜M.克兰兹，穆斯塔法·迪肯，海因里希·哈斯，塞巴斯蒂安Kreiter，卡门Loquai，克斯廷C.路透社，马丁猛，丹尼尔·弗里茨，番茄Vascotto，霍山Hefesha，基督教Grunwitz，马蒂亚斯Vormehr，伊夫Hüsemann，阿卜杜勒拉Selmi，安德烈亚斯·库恩N. ，雅尼娜降压，瑚Derhovanessian，理查德李博，塞巴斯蒂安Attig，扬狄克曼，罗伯特A. Jabulowsky，桑德拉Heesch，杰西卡·哈塞尔，彼得Langguth，斯蒂芬Grabbe等。

   
    534，
    396-401
    （2016年6月16日）
    DOI：10.1038 / nature18300

收到
    2015年12月28日
公认
    2016年05月06日
网上公布
    2016年6月1日
在线更正
    2016年6月7日



淋巴器官，其中抗原呈递细胞（APC）是在靠近给T细胞，是T细胞responses1高效引发和扩增提供了理想的微环境。然而，疫苗的全身递送抗原为树突状细胞（DC）是通过各种技术挑战阻碍。这里，我们表明，议会可精确和有效地在体内用静脉内施用的RNA脂质复合物通过最佳调整净电荷基础上公知的脂质载体（RNA-LPX），而不需要用分子配体粒子的官能化的目标。该LPX免受外核糖核酸RNA和DC群和巨噬细胞在各种淋巴车厢介导其高效吸收和编码的抗原表达。 RNA-LPX触发了由区议会浆和巨噬细胞干扰素α（IFNα）发布。因此，在原位和让人想起那些在病毒感染的早期系统性相位的炎性免疫机制DC成熟是activated2。我们表明，RNA的LPX编码病毒或突变新抗原或内源性自身抗原诱导强效应和记忆T细胞应答，并介导有效的IFNα依赖性抑制渐进肿瘤。 I期剂量递增编码共享的肿瘤抗原是正在进行的试验检测RNA-LPX。在以低剂量水平治疗的前三黑素瘤患者，IFNα和强抗原特异性T细胞应答被诱导，支持操作和效价的确定模式。任何基于多肽的抗原可以被编码为RNA3，4，RNA的LPX代表两个高度有效的自适应的全身直流指定一个普遍适用的疫苗类和同步感应以及用于癌症的I型干扰素介导的先天性免疫机制免疫治疗。
主题词：

    免疫接种
    肿瘤免疫治疗
    RNA疫苗
    疫苗
    药物输送

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