title: Lipid Nanoparticle Assisted mRNA Delivery for Potent Cancer Immunotherapy.
abstract: The induction of a strong cytotoxic T cell response is an important prerequisite for successful immunotherapy against many viral diseases and tumors. Nucleotide vaccines, including mRNA vaccines with their intracellular antigen synthesis, have been shown to be potent activators of a cytotoxic immune response. The intracellular delivery of mRNA vaccines to the cytosol of antigen presenting immune cells is still not sufficiently well understood. Here, we report on the development of a lipid nanoparticle formulation for the delivery of mRNA vaccines to induce a cytotoxic CD 8 T cell response. We show transfection of dendritic cells, macrophages, and neutrophils. The efficacy of the vaccine was tested in an aggressive B16F10 melanoma model. We found a strong CD 8 T cell activation after a single immunization. Treatment of B16F10 melanoma tumors with lipid nanoparticles containing mRNA coding for the tumor-associated antigens gp100 and TRP2 resulted in tumor shrinkage and extended the overall survival of the treated mice. The immune response can be further increased by the incorporation of the adjuvant LPS. In conclusion, 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. Further optimization, including the incorporation of different adjuvants, will likely enhance the potency of the vaccine.
authors.forename: Matthias A
authors.identifier: 0000-0002-4776-7642
authors.initials: MA
authors.lastname: Oberli
authors.forename: Andreas M
authors.initials: AM
authors.lastname: Reichmuth
authors.forename: J Robert
authors.initials: JR
authors.lastname: Dorkin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Mitchell
authors.forename: Owen S
authors.initials: OS
authors.lastname: Fenton
authors.forename: Ana
authors.initials: A
authors.lastname: Jaklenec
authors.affiliation: Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Daniel G
authors.initials: DG
authors.lastname: Anderson
authors.affiliation: Department of Anesthesiology, Boston Children's Hospital, Harvard Medical School , Boston, Massachusetts 02115, United States.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.forename: Daniel
authors.initials: D
authors.lastname: Blankschtein
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007167:Immunotherapy; D008055:Lipids / Q000737:chemistry*; D008546:Melanoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry*; D010047:Ovalbumin / Q000235:genetics; D012333:RNA, Messenger / Q000008:administration & dosage / Q000737:chemistry*; D014614:Vaccines, Synthetic / Q000276:immunology / Q000627:therapeutic use
chemical_list: D019496:Cancer Vaccines; D008055:Lipids; D012333:RNA, Messenger; D014614:Vaccines, Synthetic; D010047:Ovalbumin
keywords: cancer immunotherapy; cytotoxic T cells; immune response; lipid nanoparticles; mRNA; vaccines