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Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy : restoring the immunogenicity of immunosilent mRNA

Rein Verbeke (UGent) , Ine Lentacker (UGent) , Laura Wayteck (UGent) , Karine Breckpot, Mieke Van Bockstal (UGent) , Benedicte Descamps (UGent) , Christian Vanhove (UGent) , Stefaan De Smedt (UGent) and Heleen Dewitte (UGent)
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Abstract
This study reports on the design of mRNA and adjuvant-loaded lipid nanoparticles for therapeutic cancer vaccination. The use of nucleoside-modified mRNA has previously been shown to improve the translational capacity and safety of mRNA-therapeutics, as it prevents the induction of type I interferons (IFNs). However, type I IFNs were identified as the key molecules that trigger the activation of antigen presenting cells, and as such drive T cell immunity. We demonstrate that nucleoside-modified mRNA can be co-delivered with the clinically approved TLR agonist monophosphoryl lipid A (MPLA). As such, we simultaneously allow high antigen expression in vivo while substituting the type I IFN response by a more controllable adjuvant. This strategy shows promise to induce effective antigen-specific T cell immunity and may be useful to enhance the safety of mRNA vaccines.
Keywords
mRNA vaccination, MPLA, Adjuvant, Type I interferon, Lipid nanoparticle, Dendritic cell, LYMPH-NODE MICROENVIRONMENT, T-CELL RESPONSES, DENDRITIC CELLS, IN-VIVO, LIPID NANOPARTICLES, PROTEIN CORONA, GENE-TRANSFER, VACCINES, MICE, EXPRESSION

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Chicago
Verbeke, Rein, Ine Lentacker, Laura Wayteck, Karine Breckpot, Mieke Van Bockstal, Benedicte Descamps, Christian Vanhove, Stefaan De Smedt, and Heleen Dewitte. 2017. “Co-delivery of Nucleoside-modified mRNA and TLR Agonists for Cancer Immunotherapy : Restoring the Immunogenicity of Immunosilent mRNA.” Journal of Controlled Release  266: 287–300.
APA
Verbeke, Rein, Lentacker, I., Wayteck, L., Breckpot, K., Van Bockstal, M., Descamps, B., Vanhove, C., et al. (2017). Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy : restoring the immunogenicity of immunosilent mRNA. JOURNAL OF CONTROLLED RELEASE  , 266, 287–300.
Vancouver
1.
Verbeke R, Lentacker I, Wayteck L, Breckpot K, Van Bockstal M, Descamps B, et al. Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy : restoring the immunogenicity of immunosilent mRNA. JOURNAL OF CONTROLLED RELEASE  . 2017;266:287–300.
MLA
Verbeke, Rein, Ine Lentacker, Laura Wayteck, et al. “Co-delivery of Nucleoside-modified mRNA and TLR Agonists for Cancer Immunotherapy : Restoring the Immunogenicity of Immunosilent mRNA.” JOURNAL OF CONTROLLED RELEASE  266 (2017): 287–300. Print.
@article{8534103,
  abstract     = {This study reports on the design of mRNA and adjuvant-loaded lipid nanoparticles for therapeutic cancer vaccination. The use of nucleoside-modified mRNA has previously been shown to improve the translational capacity and safety of mRNA-therapeutics, as it prevents the induction of type I interferons (IFNs). However, type I IFNs were identified as the key molecules that trigger the activation of antigen presenting cells, and as such drive T cell immunity. We demonstrate that nucleoside-modified mRNA can be co-delivered with the clinically approved TLR agonist monophosphoryl lipid A (MPLA). As such, we simultaneously allow high antigen expression in vivo while substituting the type I IFN response by a more controllable adjuvant. This strategy shows promise to induce effective antigen-specific T cell immunity and may be useful to enhance the safety of mRNA vaccines.},
  author       = {Verbeke, Rein and Lentacker, Ine and Wayteck, Laura and Breckpot, Karine and Van Bockstal, Mieke and Descamps, Benedicte and Vanhove, Christian and De Smedt, Stefaan and Dewitte, Heleen},
  issn         = {0168-3659},
  journal      = {JOURNAL OF CONTROLLED RELEASE                                },
  language     = {eng},
  pages        = {287--300},
  title        = {Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy : restoring the immunogenicity of immunosilent mRNA},
  url          = {http://dx.doi.org/10.1016/j.jconrel.2017.09.041},
  volume       = {266},
  year         = {2017},
}

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