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Alnylam and Collaborators Publish New Pre-clinical Results on Ex Vivo Applications of RNAi to Enhance Dendritic Cell Vaccines for Cancer

RNAi Silencing of PD-1 Ligands Significantly Boosts Dendritic Cell Immunogenicity Toward Tumor Antigens

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Aug 22, 2012 - Alnylam Pharmaceuticals, Inc. (Nasdaq: 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.

About RNA Interference (RNAi)

RNAi (RNA interference) is a revolution in biology, representing a breakthrough in understanding how genes are turned on and off in cells, and a completely new approach to drug discovery and development. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and represents one of the most promising and rapidly advancing frontiers in biology and drug discovery today which was awarded the 2006 Nobel Prize for Physiology or Medicine. RNAi is a natural process of gene silencing that occurs in organisms ranging from plants to mammals. By harnessing the natural biological process of RNAi occurring in our cells, the creation of a major new class of medicines, known as RNAi therapeutics, is on the horizon. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, target the cause of diseases by potently silencing specific mRNAs, thereby preventing disease-causing proteins from being made. RNAi therapeutics have the potential to treat disease and help patients in a fundamentally new way.

About Alnylam Pharmaceuticals

Alnylam is a biopharmaceutical company developing novel therapeutics based on RNA interference, or RNAi. The company is leading the translation of RNAi as a new class of innovative medicines with a core focus on RNAi therapeutics for the treatment of genetically defined diseases, including ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. As part of its “Alnylam 5x15TM” strategy, the company expects to have five RNAi therapeutic products for genetically defined diseases in clinical development, including programs in advanced stages, on its own or with a partner by the end of 2015. Alnylam has additional partnered programs in clinical or development stages, including ALN-RSV01 for the treatment of respiratory syncytial virus (RSV) infection, ALN-VSP for the treatment of liver cancers, and ALN-HTT for the treatment of Huntington's disease. The company's leadership position on RNAi therapeutics and intellectual property have enabled it to form major alliances with leading companies including Merck, Medtronic, Novartis, Biogen Idec, Roche, Takeda, Kyowa Hakko Kirin, Cubist, and Ascletis. In addition, Alnylam and Isis co-founded Regulus Therapeutics Inc., a company focused on discovery, development, and commercialization of microRNA therapeutics; Regulus has formed partnerships with GlaxoSmithKline and Sanofi. Alnylam has also formed Alnylam Biotherapeutics, a division of the company focused on the development of RNAi technologies for applications in biologics manufacturing, including recombinant proteins and monoclonal antibodies. Alnylam's VaxiRNA™ platform applies RNAi technology to improve the manufacturing processes for vaccines; GlaxoSmithKline is a collaborator in this effort. Alnylam scientists and collaborators have published their research on RNAi therapeutics in over 100 peer-reviewed papers, including many in the world's top scientific journals such as Nature, Nature Medicine, Nature Biotechnology, and Cell. Founded in 2002, Alnylam maintains headquarters in Cambridge, Massachusetts. For more information, please visit

About “Alnylam 5x15™”

The “Alnylam 5x15” strategy, launched in January 2011, establishes a path for development and commercialization of novel RNAi therapeutics to address genetically defined diseases with high unmet medical need. Products arising from this initiative share several key characteristics including: a genetically defined target and disease; the potential to have a major impact in a high unmet need population; the ability to leverage the existing Alnylam RNAi delivery platform; the opportunity to monitor an early biomarker in Phase I clinical trials for human proof of concept; and the existence of clinically relevant endpoints for the filing of a new drug application (NDA) with a focused patient database and possible accelerated paths for commercialization. By the end of 2015, the company expects to have five such RNAi therapeutic programs in clinical development, including programs in advanced stages, on its own or with a partner. The “Alnylam 5x15” programs include ALN-TTR for the treatment of transthyretin-mediated amyloidosis (ATTR), ALN-AT3 for the treatment of hemophilia, ALN-PCS for the treatment of severe hypercholesterolemia, ALN-HPN for the treatment of refractory anemia, and ALN-TMP for the treatment of hemoglobinopathies. Alnylam intends to focus on developing and commercializing certain programs from this product strategy itself in the United States and potentially certain other countries; the company will seek development and commercial alliances for other core programs both in the United States and in other global territories.

Alnylam Forward-Looking Statements

Various statements in this release concerning Alnylam's future expectations, plans and prospects, including without limitation, statements regarding Alnylam's views with respect to the potential for RNAi therapeutics, including applications of RNAi to enhance dendritic cell vaccines for cancer and chronic viral infections, and Alnylam's expectations regarding its “Alnylam 5x15” product strategy, constitute forward-looking statements for the purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by these forward-looking statements as a result of various important factors, including, without limitation, Alnylam's ability to discover and develop novel drug candidates, successfully demonstrate the efficacy and safety of its drug candidates, including applications of RNAi to enhance dendritic cell vaccines for cancer and chronic viral infections, the pre-clinical and clinical results for these product candidates, which may not support further development of such product candidates, actions of regulatory agencies, which may affect the initiation, timing and progress of clinical trials for such product candidates, obtaining, maintaining and protecting intellectual property, obtaining regulatory approval for products, competition from others using technology similar to Alnylam's and others developing products for similar uses, and Alnylam's ability to establish and maintain strategic business alliances and new business initiatives, as well as those risks more fully discussed in the “Risk Factors” section of its most recent quarterly report on Form 10-Q on file with the Securities and Exchange Commission. In addition, any forward-looking statements represent Alnylam's views only as of today and should not be relied upon as representing its views as of any subsequent date. Alnylam does not assume any obligation to update any forward-looking statements.


Contact: Alnylam Pharmaceuticals, Inc.
Cynthia Clayton, 617-551-8207
Vice President, Investor Relations and
Corporate Communications
Amanda Sellers (Media), 202-955-6222 x2597


Posted: August 2012