Design of TOLERANT: phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis.

Autor:	Stoppelenburg AJ; Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands a.j.stoppelenburg@umcutrecht.nl.; Department of Biomolecular Health Sciences, Utrecht University Faculty of Veterinary Medicine, Utrecht, The Netherlands., Schreibelt G; Department of Medical BioSciences, Radboud University Medical Centre, Nijmegen, The Netherlands., Koeneman B; Department of Medical BioSciences, Radboud University Medical Centre, Nijmegen, The Netherlands., Welsing P; Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands., Breman EJ; Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands., Lammers L; Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands., de Goede A; Department of Pharmacy, Radboud University Medical Centre, Nijmegen, The Netherlands., Duiveman-de Boer T; Department of Medical BioSciences, Radboud University Medical Centre, Nijmegen, The Netherlands., van Eden W; Department of Biomolecular Health Sciences, Utrecht University Faculty of Veterinary Medicine, Utrecht, The Netherlands.; Trajectum Pharma B.V, Utrecht, The Netherlands., Leufkens P; Trajectum Pharma B.V, Utrecht, The Netherlands., de Vries IJM; Department of Medical BioSciences, Radboud University Medical Centre, Nijmegen, The Netherlands., Broere F; Department of Biomolecular Health Sciences, Utrecht University Faculty of Veterinary Medicine, Utrecht, The Netherlands., van Laar JM; Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands.
Jazyk:	angličtina
Zdroj:	BMJ open [BMJ Open] 2024 Sep 12; Vol. 14 (9), pp. e078231. Date of Electronic Publication: 2024 Sep 12.
DOI:	10.1136/bmjopen-2023-078231
Abstrakt:	Introduction: In rheumatoid arthritis (RA), immunosuppressive therapies may achieve symptomatic relief, but do not induce long-term, drug-free remission. Meanwhile, the lifelong use of immunosuppressive drugs confers increased risk for malignancy and infections. As such, there is an unmet need for novel treatments that selectively target the pathogenic immune response in RA by inducing tolerance to autoantigens. Autologous cell therapy using antigen-loaded tolerogenic dendritic cells (tolDCs) aims to reinstate autoantigen-specific immunological tolerance in RA and could potentially meet this need. Methods and Analysis: We report here the design of the phase I/II, investigator-initiated, open-label, dose-escalation trial TOLERANT. In this study, we will evaluate the intranodal administration of tolDCs in patients with RA that are in remission under immunosuppressive therapy. The tolDCs in this trial are loaded with the heat shock protein 70-derived peptide mB29a, which is an effective surrogate autoantigen in animal models of arthritis. Within this study, three dose-escalation cohorts (two intranodal injections of 5×10 6 , 10×10 6 and 15×10 6 tolDCs), each consisting of three patients, are evaluated to identify the highest safe dose (recommended dose), and an extension cohort of nine patients will be treated with the recommended dose. The (co-)primary endpoints of this study are safety and feasibility, which we assess by the number of AEs and the successful production of tolDCs. The secondary endpoints include the immunological effects of the treatment, which we assess with a variety of high-dimensional and antigen-specific immunological assays. Clinical effects are exploratory outcomes. Ethics and Dissemination: Ethical approval for this study has been obtained from the Netherlands Central Committee on Research Involving Human Subjects. The outcomes of the trial will be disseminated through publications in open-access, peer-reviewed scientific journals, scientific conferences and to patient associations. Trial Registration Numbers: NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register). Competing Interests: Competing interests: Trajectum Pharma B.V. has licensed IP relating to the B29 antigen from Utrecht University. AJS, FB, WvE and PL have a financial interest in Trajectum Pharma B.V. The other authors declare that they have no conflict of interest. (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
Databáze:	MEDLINE
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