Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration
Willekens B# (1,2), Presas-Rodríguez S# (3,4), Mansilla MJ (5,6), Derdelinckx J (1,2), Lee WP (7), Nijs G (7), De Laere M (2), Wens I (2), Cras P (1), Parizel P (8), Van Hecke W (9), Ribbens A (9), Billiet T (9), Adams G (10), Couttenye MM 11, Navarro-Barriuso J (5,6), Teniente-Serra A (5,6), Quirant-Sánchez B (5,6), Lopez-Diaz de Cerio A (12,13), Inogés S (12,13), Prosper F (12,14), Kip A (15), Verheij H (15), Gross CC (16,17), Wiendl H (16,17), Van Ham MS (18,19), Ten Brinke A (18,19), Barriocanal AM (20,21), Massuet-Vilamajó A (22), Hens N (23,24), Berneman Z (2,7), Martínez-Cáceres E (5), Cools N# (25,7), Ramo-Tello C# (26); RESTORE consortium.
(1) Department of Neurology, University Hospital Antwerp, Edegem, Belgium.
(2) Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp Faculty of Medicine and Health Sciences, Wilrijk, Belgium.
(3) Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
(4) Department of Medicine, Universitat Autònoma de Barcelona, Cerdanyola del Vallés, Spain.
(5) Division of Immunology, LCMN, Hospital Universitario Germans Trias i Pujol and Research Institute, Badalona, Spain.
(6) Department of Cellular Biology, Physiology and Immunology, Universitat Autònoma de Barcelona, Bellaterra, Spain.
(7) Center for Cell Therapy and Regenerative Medicine, University Hospital Antwerp, Edegem, Belgium.
(8) Department of Radiology, University Hospital Antwerp, Edegem, Belgium.
(9) Icometrix NV, Leuven, Belgium.
(10) C-Clear Partners, Mortsel, Belgium.
(11) Department of Nephrology, University Hospital Antwerp, Edegem, Belgium.
(12) Haematology-Cell Therapy Area, clinica universidad de navarra, Pamplona, Spain.
(13) Immunology and Immunotherapy Department, Clinica Universidad de Navarra, Pamplona, Spain.
(14) Program of Haematology-Oncology, CIMA, Universidad de Navarra, Pamplona, Spain.
(15) Lygature, Utrecht, The Netherlands.
(16) Department of Neurology, University Hospital Munster, Munster, Germany.
(17) Department of Neurology, University of Munster, Munster, Germany.
(18) Department of Immunopathology, Sanquin Research, Amsterdam, The Netherlands.
(19) Landsteiner Laboratory, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.
(20) Clinical Research Polyvalent Unit, Clinial Trial Unit-Spanish Clinical Research Network, Germans Trias i Pujol Health Sciences Research Institute, Badalona, Spain.
(21) Department of Pharmacology, Therapeutic and Toxicology, Universitat Autònoma de Barcelona, Cerdanyola del Vallès, Spain.
(22) Institut de Diagnòstic per la Imatge, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
(23) Interuniversity Institute for Biostatistics and statistical Bioinformatics (I-BioStat), Universiteit Hasselt, Hasselt, Belgium.
(24) Centre for Health Economic Research and Modelling Infectious Diseases, Vaccine & Infectious Disease Institute (VAXINFECTIO) & Center for Statistics, University of Antwerp Faculty of Medicine and Health Sciences, Wilrijk, Belgium.
(25) Laboratory of Experimental Hematology, Vaccine & Infectious Disease Institute (VAXINFECTIO), University of Antwerp Faculty of Medicine and Health Sciences, Wilrijk, Belgium
(26) Multiple Sclerosis Unit, Department of Neurosciences, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
# Contributed equally
Magazine: BMJ Open
Date: Sep 9, 2019Cell Therapy Area [SP]
Based on the advances in the treatment of multiple sclerosis (MS), currently available disease-modifying treatments (DMT) have positively influenced the disease course of MS. However, the efficacy of DMT is highly variable and increasing treatment efficacy comes with a more severe risk profile. Hence, the unmet need for safer and more selective treatments remains. Specifically restoring immune tolerance towards myelin antigens may provide an attractive alternative. In this respect, antigen-specific tolerisation with autologous tolerogenic dendritic cells (tolDC) is a promising approach.
METHODS AND ANALYSIS:
Here, we will evaluate the clinical use of tolDC in a well-defined population of MS patients in two phase I clinical trials. In doing so, we aim to compare two ways of tolDC administration, namely intradermal and intranodal. The cells will be injected at consecutive intervals in three cohorts receiving incremental doses of tolDC, according to a best-of-five design. The primary objective is to assess the safety and feasibility of tolDC administration. For safety, the number of adverse events including MRI and clinical outcomes will be assessed. For feasibility, successful production of tolDC will be determined. Secondary endpoints include clinical and MRI outcome measures. The patients' immune profile will be assessed to find presumptive evidence for a tolerogenic effect in vivo.
ETHICS AND DISSEMINATION:
Ethics approval was obtained for the two phase I clinical trials. The results of the trials will be disseminated in a peer-reviewed journal, at scientific conferences and to patient associations.
TRIAL REGISTRATION NUMBERS:
NCT02618902 and NCT02903537; EudraCT numbers: 2015-002975-16 and 2015-003541-26.
CITATION BMJ Open. 2019 Sep 9;9(9):e030309. doi: 10.1136/bmjopen-2019-030309
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