Abstract CT156: A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma
Authors: Jabulowsky Robert A. , Loquai Carmen , Mitzel-Rink Heidrun , Utikal Jochen , Gebhardt Christoffer , Hassel Jessica C. , Kaufmann Roland , Pinter Andreas , Derhovanessian Evelyna , Anft Christine , Attig Sebastian , Deubel Alexandra , Diken Mustafa , Gold Maike , Guertler Claudia , Haas Heinrich , Heesen Ludwig , Kemmer-Brück Alexandra , Kranz Lena M. , Kuehlcke Klaus , Kuhn Andreas , Langguth Peter , Luxemburger Ulrich , Maurus Daniel , Meng Martin , Müller Felicitas , Rae Richard , Sari Fatih , Schreeb Katharina , Schwarck-Kokarakis Doreen , Stein Malte , Jäger Dirk , Grabbe Stephan , Kreiter Sebastian , Huber Christoph , Türeci Özlem , Sahin Ugur 
Published: August 2018

Therapeutic vaccination with tumor antigen-encoding RNAs is being investigated in various clinical trials. Typically, the RNA vaccine is administered intradermally, subcutaneously or intranodally with the intention to get expression of the encoded antigens in local antigen-presenting cells (APCs).

We have developed a novel class of RNA-lipoplex (RNA(LIP)) immunotherapeutics for intravenous application, which allow systemic targeting of APCs. RNA(LIP) is a novel nanoparticulate formulation of lipid-complexed mRNA which selectively delivers the functional mRNA to APCs in lymphoid compartments body-wide for efficient mRNA uptake and expression of the encoded antigen by APCs. Moreover, this formulation has intrinsically strong adjuvant activity, mimics a systemic viral infection and induces synchronized activation of potent adaptive as well as type-I-IFN-mediated innate immune responses (Kranz et al., Nature 2016).

The first-in-human phase I/II dose escalation Lipo-MERIT trial (NCT02410733) conducted in four German study centers assesses the safety, tolerability, and biological efficacy of RNA(LIP) immunotherapy in patients with stage IIIB/C and IV melanoma. This trial is the first to investigate intravenous administration of a RNA-based cancer vaccine. Following antigen expression stratification on routinely collected tumor samples, eligible patients are treated with repeated dosing of the tetravalent Lipo-MERIT vaccine composed of RNA(LIP) products encoding the shared melanoma-associated antigens NY-ESO-1, tyrosinase, MAGE-A3, and TPTE. Pharmacodynamic activity and immunogenicity of the vaccine is investigated by concerted immune monitoring and correlative biomarker studies. Clinical activity is assessed following imaging according to irRECIST1.1.

As of January 2018, &gt;50 patients have been treated with escalating or constant dosing under the guidance of an independent data safety and monitoring board. The Lipo-MERIT vaccine was generally well-tolerated and no dose-limiting toxicities (DLTs) were observed so far. Further patient enrollment is continuing.

Preliminary data on the assessment of vaccine-induced immune responses and clinical responses from the first patients treated will be presented.

Citation Format: Robert A. Jabulowsky, Carmen Loquai, Heidrun Mitzel-Rink, Jochen Utikal, Christoffer Gebhardt, Jessica C. Hassel, Roland Kaufmann, Andreas Pinter, Evelyna Derhovanessian, Christine Anft, Sebastian Attig, Alexandra Deubel, Mustafa Diken, Maike Gold, Claudia Guertler, Heinrich Haas, Ludwig Heesen, Alexandra Kemmer-Brück, Lena M. Kranz, Klaus Kuehlcke, Andreas Kuhn, Peter Langguth, Ulrich Luxemburger, Daniel Maurus, Martin Meng, Felicitas Müller, Richard Rae, Fatih Sari, Katharina Schreeb, Doreen Schwarck-Kokarakis, Malte Stein, Dirk Jäger, Stephan Grabbe, Sebastian Kreiter, Christoph Huber, Özlem Türeci, Ugur Sahin. A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT156.