Department of Rheumatology & Clinical Immunology, University Medical Centre Utrecht, Utrecht, The Netherlands
Department of Biomolecular Health Sciences, Utrecht University Faculty of Veterinary Medicine, Utrecht, The Netherlands.
BMJ Open. 2024 Sep 12;14(9):e078231. doi: 10.1136/bmjopen-2023-078231.
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.
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, 10×10 and 15×10 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.
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.
NCT05251870; 2019-003620-20 (EudraCT); NL71296.000.20 (CCMO register).
在类风湿关节炎（RA）中，免疫抑制疗法可以缓解症状，但不能诱导长期、无需药物的缓解。同时，终生使用免疫抑制剂会增加恶性肿瘤和感染的风险。因此，人们迫切需要新的治疗方法，通过诱导对自身抗原的免疫耐受，选择性地靶向 RA 中的致病性免疫反应。使用负载抗原的耐受性树突状细胞（tolDCs）的自体细胞疗法旨在恢复 RA 中的自身抗原特异性免疫耐受，并且可能能够满足这一需求。
我们在此报告了 I/II 期、研究者发起的、开放标签、剂量递增试验 TOLERANT 的设计。在这项研究中，我们将评估在接受免疫抑制治疗缓解期的 RA 患者中节点内给予 tolDCs 的效果。该试验中的 tolDCs 负载热休克蛋白 70 衍生肽 mB29a，这是关节炎动物模型中的一种有效替代自身抗原。在这项研究中，三个剂量递增队列（两次节点内注射 5×10、10×10 和 15×10 tolDCs），每个队列包含 3 名患者，将用于确定最高安全剂量（推荐剂量），并对 9 名患者进行推荐剂量的扩展队列治疗。该研究的主要和次要终点是安全性和可行性，我们通过不良事件的数量和 tolDCs 的成功生产来评估。次要终点包括治疗的免疫学效应，我们使用各种高维的和抗原特异性的免疫学检测来评估。临床效果是探索性结果。
这项研究已获得荷兰人体研究中央伦理委员会的批准。试验结果将通过在开放获取、同行评议的科学期刊、科学会议和患者协会上发表来传播。
NCT05251870；2019-003620-20（EudraCT）；NL71296.000.20（CCMO 登记）。
