Particle-mediated Intravenous Delivery of Antigen mRNA Results in Strong Antigen-specific T-cell Responses Despite the Induction of Type I Interferon

  title={Particle-mediated Intravenous Delivery of Antigen mRNA Results in Strong Antigen-specific T-cell Responses Despite the Induction of Type I Interferon},
  author={Katrijn Broos and Kevin Van der Jeught and Janik Puttemans and Cleo Goyvaerts and Carlo Heirman and Heleen Dewitte and Rein Verbeke and Ine Lentacker and Kris Thielemans and Karine Breckpot},
  journal={Molecular Therapy. Nucleic Acids},
Cancer vaccines based on mRNA are extensively studied. The fragile nature of mRNA has instigated research into carriers that can protect it from ribonucleases and as such enable its systemic use. However, carrier-mediated delivery of mRNA has been linked to production of type I interferon (IFN) that was reported to compromise the effectiveness of mRNA vaccines. In this study, we evaluated a cationic lipid for encapsulation of mRNA. The nanometer-sized, negatively charged lipid mRNA particles… 
Efficient Targeting and Activation of Antigen-Presenting Cells In Vivo after Modified mRNA Vaccine Administration in Rhesus Macaques
Cationic lipid-assisted nanoparticles for delivery of mRNA cancer vaccine.
Investigation of cationic lipid-assisted nanoparticles (CLAN) found that CLAN encapsulating mRNA encoding antigen could effectively stimulate the maturation of dendritic cells and promote the activation and proliferation of antigen-specific T cells both in vitro and in vivo.
Type I Interferons Interfere with the Capacity of mRNA Lipoplex Vaccines to Elicit Cytolytic T Cell Responses.
It is demonstrated that mRNA lipoplexes induce a potent type I interferon response upon subcutaneous, intradermal and intranodal injection and blocking type I IFN signaling at the site of immunization through the use of an IFNAR blocking antibody greatly enhanced the prophylactic and therapeutic antitumor efficacy of mRNAlipoplexes in the highly aggressive B16 melanoma model.
Delivery of mRNA vaccines with heterocyclic lipids increases anti-tumor efficacy by STING-mediated immune cell activation
A combinatorial library of ionizable lipid-like materials is developed to identify mRNA delivery vehicles that facilitate mRNA delivery in vivo and provide potent and specific immune activation, and result in limited systemic cytokine expression and enhanced anti-tumor efficacy.
Systemic activation of antigen-presenting cells via RNA-loaded nanoparticles
Although cancer vaccines have suffered from weak immunogenicity, a RNA-NP formulation is advanced that systemically activates host APCs precipitating activated T-cell frequencies necessary to engender antitumor efficacy and can thus be harnessed as a more feasible and effective immunotherapy to re-program host-immunity.
Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy.
The lipid nanoparticle formulation presented here is a promising vector for mRNA vaccine delivery, one that is capable of inducing a strong cytotoxic T cell response and further optimization, including the incorporation of different adjuvants, will likely enhance the potency of the vaccine.
Tethering designer short double-stranded RNA to mRNA for co-delivery of molecularly-targeted adjuvants and antigens towards cancer vaccination
The optimal mRNA formulation improved the potency of mRNA vaccine to induce cytotoxic immune responses after encapsulation into mRNA lipoplex, and exhibited high therapeutic efficiency in lung metastatic model of melanoma using mRNA encoding tumor associated antigen.


Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines.
It is demonstrated that subcutaneous immunization of mice with mRNA encoding the HIV-1 antigen Gag complexed with DOTAP/DOPE elicits antigen-specific, functional T cell responses resulting in specific killing of Gag peptide-pulsed cells and the induction of humoral responses.
Vaccination with messenger RNA (mRNA).
  • S. Pascolo
  • Biology
    Handbook of experimental pharmacology
  • 2008
The structure of mRNA, its possible optimizations for immunization purposes, the different methods of delivery used in preclinical studies, and finally the results of clinical trial where mRNA is the active pharmaceutical ingredient of new innovative vaccines are described.
Induction of virus‐specific cytotoxic T lymphocytes in vivo by liposome‐entrapped mRNA
The induction of anti‐influenza cytotoxic T lymphocytes (CTL) in vivo by immunizing mice with liposomes containing messenger RNA (mRNA) encoding the influenza virus nucleoprotein (NP) is described and the relevance of these results in the context of vaccine development is discussed.
Preclinical evaluation of TriMix and antigen mRNA-based antitumor therapy.
In several mouse tumor models, mRNA vaccination was as efficient in CTL induction and therapy response as vaccination with mRNA-electroporated DCs, suggesting that intranodal administration of TAA mRNA together with mRNA encoding immunomodulating molecules is a promising vaccination strategy.
Messenger RNA-based Vaccines With Dual Activity Induce Balanced TLR-7 Dependent Adaptive Immune Responses and Provide Antitumor Activity
A two-component mRNA-based tumor vaccine that supports both: antigen expression and immune stimulation, mediated by Toll like receptor 7 (TLR7), and induce balanced adaptive immune responses providing humoral as well as T cell mediated immunity is presented.
mRNA: delivering an antitumor message?
This study highlights the potential of mRNA vaccines to induce immune responses and mediate sustained antitumor activity in both prophylactic and therapeutic settings.
Selective uptake of naked vaccine RNA by dendritic cells is driven by macropinocytosis and abrogated upon DC maturation
It is observed that RNA is rapidly and selectively uptaken by lymph node dendritic cells (DCs), implying that bioavailability of recombinant RNA vaccines in vivo highly depends on the density and the maturation stage of DCs at the administration site and are of importance for the design of RNA-based clinical immunotherapy protocols.
Intranodal vaccination with naked antigen-encoding RNA elicits potent prophylactic and therapeutic antitumoral immunity.
In tumor-bearing mice intralymphatic RNA vaccination elicited protective and therapeutic antitumor immune responses, resulting in a remarkable survival benefit as compared with other treatment regimens.
Intratumoral administration of mRNA encoding a fusokine consisting of IFN-β and the ectodomain of the TGF-β receptor II potentiates antitumor immunity
It is suggested that intratumoral delivery of mRNA encoding soluble proteins, such as Fβ2, can modulate the tumor microenvironment, leading to effective antitumor T cell responses, which can be further potentiated through combination therapy.
Expression of therapeutic proteins after delivery of chemically modified mRNA in mice
In a mouse model of a lethal congenital lung disease caused by a lack of surfactant protein B (SP-B), twice weekly local application of an aerosol of modified SP-B mRNA to the lung restored 71% of the wild-type SP- B expression, and treated mice survived until the predetermined end of the study after 28 days.