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

Rein Verbeke; Ine Lentacker; Laura Wayteck; Karine Breckpot; Mieke Van Bockstal; Benedicte Descamps; Christian Vanhove; Stefaan C De Smedt; Heleen Dewitte

doi:10.1016/j.jconrel.2017.09.041

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

J Control Release. 2017 Nov 28:266:287-300. doi: 10.1016/j.jconrel.2017.09.041. Epub 2017 Oct 5.

Authors

Rein Verbeke¹, Ine Lentacker¹, Laura Wayteck¹, Karine Breckpot², Mieke Van Bockstal³, Benedicte Descamps⁴, Christian Vanhove⁴, Stefaan C De Smedt⁵, Heleen Dewitte⁶

Affiliations

¹ Ghent Research Group on Nanomedicines, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
² Laboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Medical School of the Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1050 Jette, Belgium.
³ Department of Pathology, Ghent University Hospital, De Pintelaan 18, 9000 Ghent, Belgium.
⁴ Infinity Lab, Institute Biomedical Technology, Medical Imaging and Signal Processing, Ghent University, De Pintelaan 185, 9000 Ghent, Belgium.
⁵ Ghent Research Group on Nanomedicines, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: Stefaan.DeSmedt@UGent.be.
⁶ Ghent Research Group on Nanomedicines, Faculty of Pharmacy, Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium; Cancer Research Institute Ghent (CRIG), Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium; Laboratory for Molecular and Cellular Therapy, Department of Biomedical Sciences, Medical School of the Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1050 Jette, Belgium.

PMID: 28987878
DOI: 10.1016/j.jconrel.2017.09.041

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: 5-Methylcytidine (PubChem CID: 92918); Adjuvant; CFSE (PubChem CID: 16211581); Cholesterol (PubChem CID: 5997); DOPE (PubChem CID: 9546757); DOTAP (PubChem CID: 6437371); Dendritic cell; Lipid nanoparticle; MPLA; MPLA (PubChem CID: 5043498); Pseudouridine (PubChem CID: 57369533); SIINFEKL (PubChem CID: 71311993); Type I interferon; mRNA vaccination.

MeSH terms

Animals
Cancer Vaccines
Cytidine / administration & dosage
Cytidine / analogs & derivatives*
Cytidine / chemistry
Dendritic Cells / immunology
Female
Immunotherapy
Lipid A / administration & dosage
Lipid A / analogs & derivatives*
Lipids / administration & dosage
Lipids / chemistry
Mice, Inbred C57BL
Neoplasms / immunology
Neoplasms / therapy*
RNA, Messenger / administration & dosage*
RNA, Messenger / chemistry
RNA, Messenger / immunology
Toll-Like Receptors / agonists*

Substances

Cancer Vaccines
Lipid A
Lipids
RNA, Messenger
Toll-Like Receptors
Cytidine
monophosphoryl lipid A
5-methylcytidine