TY - JOUR
T1 - Design of TOLERANT
T2 - phase I/II safety assessment of intranodal administration of HSP70/mB29a self-peptide antigen-loaded autologous tolerogenic dendritic cells in patients with rheumatoid arthritis
AU - Stoppelenburg, Arie Jan
AU - Schreibelt, Gerty
AU - Koeneman, Bouke
AU - Welsing, Paco M J
AU - Breman, Evert-Jan
AU - Lammers, Laureen
AU - de Goede, Anna
AU - Duiveman-de Boer, Tjitske
AU - van Eden, Willem
AU - Leufkens, Paul
AU - de Vries, I Jolanda M
AU - Broere, Femke
AU - van Laar, Jacob M
N1 - Publisher Copyright:
© 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.
PY - 2024/9/12
Y1 - 2024/9/12
N2 - 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).
AB - 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).
KW - clinical trial
KW - immunology
KW - rheumatology
UR - http://www.scopus.com/inward/record.url?scp=85204058684&partnerID=8YFLogxK
U2 - 10.1136/bmjopen-2023-078231
DO - 10.1136/bmjopen-2023-078231
M3 - Article
C2 - 39266308
SN - 2044-6055
VL - 14
JO - BMJ Open
JF - BMJ Open
IS - 9
M1 - e078231
ER -