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

• Published in: BMJ open Vol. 14; no. 9; p. e078231
• Main Authors: Stoppelenburg, Arie Jan, Schreibelt, Gerty, Koeneman, Bouke, Welsing, Paco, Breman, Evert-Jan, Lammers, Laureen, de Goede, Anna, Duiveman-de Boer, Tjitske, van Eden, Willem, Leufkens, Paul, de Vries, I Jolanda M, Broere, Femke, van Laar, Jacob M
• Format: Journal Article
• Language: English
• Published: England British Medical Journal Publishing Group 12.09.2024; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Adult; Antigens; Arthritis, Rheumatoid - drug therapy; Arthritis, Rheumatoid - immunology; Arthritis, Rheumatoid - therapy; Autoantigens - immunology; Autoimmune diseases; Cartilage; clinical trial; Clinical trials; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Dendritic cells; Dendritic Cells - immunology; Diabetes; Disease; Drug dosages; Female; Good Manufacturing Practice; Heat shock proteins; HSP70 Heat-Shock Proteins - immunology; Humans; Immune Tolerance; Immunology; Inflammation; Leukocytes; Lymphocytes; Male; Middle Aged; Multiple sclerosis; Peptides; Protocol; Remission (Medicine); Rheumatoid arthritis; Rheumatology; Transplantation, Autologous; Tumor necrosis factor-TNF; clinical trial; rheumatology; immunology
• ISSN: 2044-6055; 2044-6055
• DOI: 10.1136/bmjopen-2023-078231

IntroductionIn 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 analysisWe 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 5×106, 10×106 and 15×106 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 disseminationEthical 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 numbersNCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).