Abstract CT034: A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles for potent melanoma immunotherapy

Therapeutic vaccination with tumor antigen-encoding RNAs by local administration is currently being successfully employed in various clinical trials. Advancing from local to more efficient systemic targeting of antigen-presenting cells (APCs), we have developed pioneering RNA-lipoplex (RNA(LIP)) immunotherapeutics for intravenous application based on the employment of well-known lipid carriers without the need for functionalization of particles with molecular ligands. The novel RNA(LIP) formulation has been engineered to preserve RNA integrity after intravenous injection and physicochemically optimized for efficient uptake and expression of the encoded antigen by APCs in various lymphoid compartments, resulting in the synchronized induction of both potent adaptive as well as type-I-IFN-mediated innate immune responses. The first-in-human phase I/II dose escalation Lipo-MERIT trial (NCT02410733) assesses the safety, tolerability, and biological efficacy of the innovative RNA(LIP) immunotherapy in four study centers in Germany. This is the first example of a clinically applicable and systemic RNA-based cancer vaccine. Following selective antigen stratification on routinely collected tumor samples, eligible patients with malignant melanoma are treated with increasing doses of the tetravalent Lipo-MERIT vaccine - a fixed set of four RNA(LIP) products, each encoding one shared melanoma-associated antigen, i.e. NY-ESO-1, tyrosinase, MAGE-A3, and TPTE, that are administered successively within one treatment cycle. Accompanying correlative biomarker studies and concerted immunological assessments evaluate the pharmacodynamic activity and immunogenicity upon multiple vaccination cycles with the Lipo-MERIT vaccine. As of January 2017, 15 patients have been treated within five dose escalation cohorts thoroughly guided by an independent data safety and monitoring board. Multiple dosing with the Lipo-MERIT vaccine was generally well-tolerated and no dose-limiting toxicities (DLTs) were observed so far. Further patient enrollment is continuing. Detailed information on the ongoing trial, the recruitment and treatment status as well as preliminary data on the assessment of vaccine-induced immune responses from the first patients treated will be presented. Citation Format: Robert A. Jabulowsky, Carmen Loquai, Jochen Utikal, Jessica Hassel, Roland Kaufmann, Evelyna Derhovanessian, Mustafa Diken, Lena M. Kranz, Heinrich Haas, Sebastian Attig, Christine Anft, Janina Buck, Jan Diekmann, Daniel Fritz, Kerstin Hartmann, Alexandra Kemmer-Brueck, Klaus Kuehlcke, Andreas N. Kuhn, Peter Langguth, Ulrich Luxemburger, Martin Meng, Richard Rae, Fatih Sari, Doreen Schwarck-Kokarakis, Malte Stein, Stephan Grabbe, Sebastian Kreiter, Oezlem Tuereci, Christoph Huber, Ugur Sahin. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles for potent melanoma immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT034. doi:10.1158/1538-7445.AM2017-CT034