mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cures established tumors in mice.

Autor:	Haabeth OAW; Stanford Cancer Institute, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305.; Department of Immunology and Transfusion Medicine, Oslo University Hospital, 0020 Oslo, Norway., Blake TR; Department of Chemistry, Stanford University, Stanford, CA 94305., McKinlay CJ; Department of Chemistry, Stanford University, Stanford, CA 94305., Waymouth RM; Department of Chemistry, Stanford University, Stanford, CA 94305., Wender PA; Department of Chemistry, Stanford University, Stanford, CA 94305.; Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305., Levy R; Stanford Cancer Institute, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305; levy@stanford.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Sep 25; Vol. 115 (39), pp. E9153-E9161. Date of Electronic Publication: 2018 Sep 10.
DOI:	10.1073/pnas.1810002115
Abstrakt:	In vivo delivery of antigen-encoding mRNA is a promising approach to personalized cancer treatment. The therapeutic efficacy of mRNA vaccines is contingent on safe and efficient gene delivery, biological stability of the mRNA, and the immunological properties of the vaccine. Here we describe the development and evaluation of a versatile and highly efficient mRNA vaccine-delivery system that employs charge-altering releasable transporters (CARTs) to deliver antigen-coding mRNA to antigen-presenting cells (APCs). We demonstrate in human peripheral blood mononuclear cells that CART vaccines can activate a robust antigen-specific immune response against mRNA-encoded viral epitopes. In an established mouse model, we demonstrate that CARTs preferentially target professional APCs in secondary lymphoid organs upon i.v. injections and target local APCs upon s.c. injection. Finally, we show that CARTs coformulated with mRNA and a Toll-like receptor ligand simultaneously transfect and activate target cells to generate an immune response that can treat and cure mice with large, established tumors. Competing Interests: Conflict of interest statement: Reviewers P.M.S. and M.C. and author R.L. are coauthors of a 2016 review article.
Databáze:	MEDLINE
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