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

The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potenti...

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Vydáno v:	Nature (London) Ročník 534; číslo 7607; s. 396 - 401
Hlavní autoři:	Kranz, Lena M., Diken, Mustafa, Haas, Heinrich, Kreiter, Sebastian, Loquai, Carmen, Reuter, Kerstin C., Meng, Martin, Fritz, Daniel, Vascotto, Fulvia, Hefesha, Hossam, Grunwitz, Christian, Vormehr, Mathias, Hüsemann, Yves, Selmi, Abderraouf, Kuhn, Andreas N., Buck, Janina, Derhovanessian, Evelyna, Rae, Richard, Attig, Sebastian, Diekmann, Jan, Jabulowsky, Robert A., Heesch, Sandra, Hassel, Jessica, Langguth, Peter, Grabbe, Stephan, Huber, Christoph, Türeci, Özlem, Sahin, Ugur
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 16.06.2016 Nature Publishing Group
Témata:	13/109 13/21 13/31 14/1 14/19 14/28 14/5 631/250/251/1567 631/250/590 631/250/590/2293 631/67/1059/2325 639/925/352/152 64/110 64/60 Administration, Intravenous Animals Antigen Presentation - immunology Antigens Antigens, Neoplasm - genetics Antigens, Neoplasm - immunology Antigens, Viral - genetics Antigens, Viral - immunology Autoantigens - genetics Autoantigens - immunology Cancer Cancer therapies Cancer Vaccines - administration & dosage Cancer Vaccines - genetics Care and treatment Clinical Trials, Phase I as Topic Dendritic cells Dendritic Cells - cytology Dendritic Cells - immunology Dendritic Cells - metabolism Disease Models, Animal Drug Carriers - administration & dosage Drug delivery systems Drugs Female Gene expression Genetic aspects Health aspects Humanities and Social Sciences Humans Immunotherapy Immunotherapy - methods Innovations Interferon Type I - immunology Interferon Type I - secretion letter Lipids Lungs Lymphatic system Lymphocyte Activation - immunology Lymphoid Tissue - cytology Lymphoid Tissue - immunology Macrophages - immunology Macrophages - metabolism Male Melanoma Melanoma - immunology Melanoma - therapy Membrane Glycoproteins - immunology Methods Mice Mice, Inbred C57BL Mode of action Molecular targeted therapy multidisciplinary Nanoparticles - administration & dosage Ribonucleic acid RNA RNA - administration & dosage RNA - genetics Science Spleen Static Electricity T-Lymphocytes - cytology T-Lymphocytes - immunology Toll-Like Receptor 7 - immunology Vaccines Vehicles
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	The development of a nanoparticle RNA vaccine is reported that preferentially targets dendritic cells after systemic administration, and is shown to provide durable interferon-α-dependent antigen-specific immunity in mouse tumour models; initial results in advanced melanoma patients indicate potential efficacy in humans. An anti-cancer nanoparticulate RNA vaccine The systemic delivery of vaccine antigens into the dendritic or antigen-presenting cells of the immune system faces many technical challenges. This study reports the development of a nanoparticle RNA vaccine that preferentially targets dendritic cells after systemic administration. The vaccine consists of RNA-lipoplexes based on well-known lipid carriers; targeting is achieved by optimally adjusting the negative net charge of the nanoparticles, with no need for functionalization with molecular ligands. Intravenous administration produces durable type-I-interferon-dependent antigen-specific immunity in mouse tumour models. Initial results in patients with advanced melanoma indicate potential efficacy in humans. Virtually any tumour antigen can be encoded by RNA, so this approach is potentially more generally applicable in cancer immunotherapy. 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 responses 1 . 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 activated 2 . 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 RNA 3 , 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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/nature18300