1944 - A first-in-human phase I/II clinical trial assessing novel mRNA-lipoplex nanoparticles encoding shared tumor antigens for immunotherapy of malignant melanoma

Background

Local therapeutic vaccination with tumor antigen-encoding mRNAs is being investigated in various clinical trials. We have developed a novel class of RNA-lipoplex (RNA_(LIP)) immunotherapeutics for intravenous application allowing systemic targeting of antigen-presenting cells (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).

Trial design

The first-in-human phase I/II dose escalation Lipo-MERIT trial (NCT02410733) is the first clinical trial to investigate the intravenous administration of a RNA-based cancer vaccine. The trial assesses the safety and tolerability of systemic RNA_(LIP) immunotherapy in patients with stage IIIB/C and IV melanoma in four German study centers. 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 based on the expression of at least one of these antigens in routinely collected patientś tumor samples. Patients in dose escalation cohorts (classical 3 + 3 design) follow a step-up dosing towards different target doses. 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.

Clinical trial identification

EudraCT: 2013-001646-33.

Legal entity responsible for the study

BioNTech RNA Pharmaceuticals GmbH.

Funding

Has not received any funding.

Editorial Acknowledgement

Disclosure

R.A. Jabulowsky, E. Derhovanessian, M. Diken, M. Gold, K.H. Schreeb, D. Schwarck-Kokarakis, S. Kreiter: Employee: BioNTech; Patent ownership, patent applications, stock ownership. C. Loquai: Roche, Novartis, Pierre Fabre, MSD, BMS, Leo, Amgen, Biontech. J. Utikal: Amgen, Biontech, BMS, GSK, MSD, Novartis, Roche, Rheacell, Evalys. J. Hassel: Consulting or advisory role: BioNTech AG, BMS, Roche, Novartis, Pierre Fabre, Philogen, Amgen, ImmunoCore. R. Kaufmann: Merz, Roche, Regeneron, Novartis, Amgen, BMS, Icon, Actelion, Abbvie, Allmiral, Biogen, Idec, Boehringer, Celgene, GSK, Lily, Galderma, LEO, Medac, Merck, Mitsubishi, MSD, Pfizer, TigerCat, Sandoz, Shering, UCB. A. Pinter: AbbVie, AstraZeneca, Biogen, Boehringer Ingelheim, BMS, Celgene, GSK, Janssen-Cilag, LEO Pharma, Lilly Pharma, Novartis, MSD, Regeneron, Roche, Tigercat, UCB. L. Heesen: Employee: BioNTech. D. Jäger: Amgen, Bayer, BMS, Curevac, MSD, Roche. S. Grabbe: Roche, Novartis, MSD, BMS. Ö. Türeci: BioNTech, patent ownership, patent applications, Stock ownership. U. Sahin: Founder, patent ownership, patent applications, Stock ownership: BioNTech. All other authors have declared no conflicts of interest.