Pre-clinical Results on Ex Vivo Applications of RNAi to Enhance Dendritic Cell Vaccines for Cancer
Alnylam Pharmaceuticals, Inc. (ALNY), a leading RNAi therapeutics company, and collaborators at Radboud University Nijmegen Medical Centre in the Netherlands announced today that they have published new pre-clinical results in the journal Cancer Immunology Immunotherapy (doi:10.1007/s00262-012-1334-1) describing the development of a dendritic cell (DC) cancer vaccine with enhanced immunogenic potential. The findings show that ex vivo RNAi targeting of the programmed death ligands (PD-L1 and PD-L2) can significantly boost the immunogenicity of DC-based vaccines. These results could lead to the development of improved cellular vaccine therapies for the treatment of cancer and chronic viral infections.
“At Alnylam, we continue to pioneer broad applications of RNAi in biotechnology and human health, while our core focus remains the advancement of RNAi therapeutics in our ‘Alnylam 5x15’ product strategy,” said Rachel Meyers, Ph.D., Vice President, Research and RNAi Lead Development. “These new results demonstrate the potential of an ex vivo RNAi approach to strongly improve the immunogenicity of dendritic cell vaccines toward tumor antigens. As such, this new strategy could significantly enhance the potency of cellular immune therapy in cancer, and potentially other indications such as infectious disease.”
“While much progress has been made in the development of dendritic cell vaccines in cancer, there is a clear need to improve this strategy for increased clinical benefit. Specifically, further advancement of dendritic cell therapies requires an enhanced potency of the T-cell anti-tumor responses,” said Harry Dolstra, Ph.D., Associate Professor at Radboud University Nijmegen Medical Centre, Laboratory of Hematology. “These new findings show that a relatively simple ex vivo RNAi approach may be able to boost the effectiveness of cellular therapies in the treatment of cancer, and possibly chronic viral infections. We look forward to advancing this novel approach in clinical studies.”
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.