mRNA vaccination with charge-altering releasable transporters elicits human T cell responses and cur | DVAX Message Board Posts

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Msg  1242 of 1634  at  10/2/2018 8:23:53 AM  by

fairvalueforyou

The following message was updated on 10/2/2018 8:24:27 AM.

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

 
 
Ole A. W. Haabeth, Timothy R. Blake, Colin J. McKinlay, Robert M. Waymouth, Paul A. Wender, and Ronald Levy
 
 

Significance

The RNA delivery field is mostly focused on lipid nanoparticles (LNPs). Although promising, LNPs have several limitations with respect to pharmacokinetics, biodistribution, and toxicity. The mechanism of RNA charge-altering releasable transporters (CART) delivery and release is unique. It proceeds dynamically with a controllable change in physical properties. Differing from all mRNA delivery systems, a key attribute of CARTs is a charge-altering degradation mechanism, which transforms the initial polycationic CART into neutral byproducts, thereby enabling endosomal escape, release, and subsequent translation of the polyanionic mRNA cargo. With this study, we introduce a potentially general approach to therapeutic vaccination enabled by a dynamic drug-delivery system (mRNA-CART) and demonstrate its utility in suppressing tumor formation and in eliminating established tumors.

Abstract

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.
 
 


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