Abstract A004: Systemic RNA vaccines: Connecting effective cancer immunotherapy with antiviral defense mechanisms

• Published in: Cancer immunology research 2016-11, Vol.4 (11_Supplement), p.A004-A004
• Main Authors: Kranz, Lena M., Diken, Mustafa, Haas, Heinrich, Kreiter, Sebastian, Loquai, Carmen, Reuter, Kerstin C., Meng, Martin, Fritz, Daniel, Vascotto, Fulvia, Hefesha, Hossam, Grunwitz, Christian, Vormehr, Mathias, Hüsemann, Yves, Selmi, Abderraouf, Kuhn, Andreas N., Buck, Janina, Derhovanessian, Evelyna, Rae, Richard, Attig, Sebastian, Diekmann, Jan, Jabulowsky, Robert A., Heesch, Sandra, Hassel, Jessica, Langguth, Peter, Grabbe, Stephan, Huber, Christoph, Türeci, Özlem, Sahin, Ugur
• Format: Article
• Language: English
• ISSN: 2326-6066; 2326-6074
• DOI: 10.1158/2326-6066.IMM2016-A004

Mechanisms of antiviral host defense are important for survival and evolutionarily optimized for high sensitivity and potency. Intending to harvest the multitude of highly specialized and intertwined pathogen immune defense programs for cancer immunotherapy, we simulated a systemic pathogen intrusion into the blood stream by intravenous injection of lipid-formulated, tumor antigen-encoding mRNA nanoparticles. These RNA-lipoplexes (RNA-LPX) were directed to various lymphoid tissues, including the spleen, lymph nodes and bone marrow, which provide the ideal microenvironment for efficient priming and amplification of T cell responses. Solely the RNA-to-lipid ratio was discovered to determine the biodistribution of RNA-LPX, irrespective of the types of lipids used, and a slightly negative particle net charge was able to specifically transfect lymphoid-resident antigen presenting cells (APCs). Following uptake by CD11c+ DCs, pDCs and macrophages in the marginal zone of the spleen and in other lymphoid organs, predominantly by macropinocytosis, RNA recognition via TLR7 triggered two transient waves of type I IFN production by pDCs (early response) and macrophages (delayed response), which established an inflammatory, lymphocyte-activating milieu reminiscent of that initiated during the early systemic phase of viral infection. These IFNα receptor (IFNAR)-dependent immune mechanisms were required for DCs to mature, migrate into the T cell zones and express RNA-encoded tumor antigens. Presentation on MHC class I and II in the context of upregulated CD40, CD69 and CD86 elicited strong effector and memory CD8 and CD4 T cell immunity against viral, mutant neo-antigens or self-antigens, which was able to reject progressive tumors in therapeutic mouse models of melanoma, colon carcinoma and human papilloma virus (HPV)-associated cancer. In an ongoing phase I dose escalation study, the first cohort of three patients with advanced melanoma received RNA-LPX encoding four shared tumor antigens at doses lower than those used in the mouse studies. All patients showed a dose-dependent IFNα- and IP-10-dominated cytokine response, developed de novo CD4 and CD8 T cell responses or enhanced pre-existing immunity against the encoded self-antigens NY-ESO-I, Tyrosinase and MAGE-A3, and have stable disease to date. These results support the preclinically identified mode of action and strong potency of this approach in the clinical setting. Our study presents a novel class of systemica