Haabeth et al. developed a vaccine strategy in which cationic, charge-altering, releasable transporters (CARTs) are co-formulated with antigen-encoding mRNA and CpG adjuvant. In human PBMCs and mouse models, mRNA-CART effectively delivered antigen-encoding mRNA to antigen-presenting cells and activated antigen-specific CD4+ and CD8+ T cell responses. mRNA-CART vaccines exhibited efficacy and durable protection when administered at the time of tumor implant. In mice with medium or large established tumors, mRNA-CART led to complete regression in 80% and 40% of mice, respectively, and extended median survival.
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.
Author Info: (1) Stanford Cancer Institute, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305. Department of Immunology and Transfusion Medicine, Oslo Univer
Author Info: (1) 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. (2) Department of Chemistry, Stanford University, Stanford, CA 94305. (3) Department of Chemistry, Stanford University, Stanford, CA 94305. (4) Department of Chemistry, Stanford University, Stanford, CA 94305. (5) Department of Chemistry, Stanford University, Stanford, CA 94305. Department of Chemical and Systems Biology, Stanford University, Stanford, CA (6) Stanford Cancer Institute, Division of Oncology, Department of Medicine, Stanford University, Stanford, CA 94305; levy@stanford.edu.
