8:02AM Alnylam Pharma and collaborators publish new pre-clinical results on Ex Vivo Applications of RNAi to enhance dendritic cell vaccines for Cancer says 'Ex vivo treatment with siRNA was well tolerated by the isolated DC (ALNY) 17.94 : Co announced that NAi Silencing of PD-1 Ligands Significantly Boosts Dendritic Cell Immunogenicity Toward Tumor Antigens. The new results describe development of a clinical-grade DC vaccine with improved immunogenic potential. Potent siRNA were designed and synthesized toward PD-L1 and PD-L2, key co-inhibitory proteins expressed on antigen-presenting cells that strongly limit activation of T-cells needed for a potent immune response to the tumor. Specifically, lipid nanoparticle (LNP)-formulated siRNA targeting PD-L1 and PD-L2 mediated efficient and specific silencing of PD-L1 and PD-L2 expression on human monocyte-derived DC isolated from healthy donors. Ex vivo treatment with siRNA was well tolerated by the isolated DC, with no measurable effect on phenotype or migratory capacity. Further, siRNA-treated DC were loaded by electroporation with mRNA encoding minor histocompatibility antigen (MiHA) to allow long-lasting presentation of antigenic peptides expressed by malignant cells. The combined LNP siRNA transfection electroporation protocol was found to be well tolerated by the isolated DC. The resulting PD-L silenced, MiHA-expressing DCs were shown to have a significantly enhanced ability to stimulate antigen-specific CD8+ T cell responses in cells from transplanted cancer patients ex vivo. This novel RNAi approach has potential implications for the treatment of cancer and chronic viral infections, where an improvement in DC vaccine potency is needed
