Central Research Center, Corestem Inc, Seoul, Republic of Korea.
Department of Rheumatology, 26716Hanyang University Hospital for Rheumatic Diseases, Hanyang University Institute for Rheumatology Research, and Hanyang University Institute of Bioscience and Biotechnology, Seoul, Republic of Korea.
Lupus. 2022 Sep;31(10):1245-1253. doi: 10.1177/09612033221111957. Epub 2022 Jul 8.
Several clinical trials aimed at treating various autoimmune diseases, including systemic lupus erythematosus (SLE), by introducing mesenchymal stem cells (MSCs) have been conducted. However, with refractory lupus nephritis (LN), the outcomes of MSC transplantation are not well known, and further validation is required. In particular, data concerning the safety and efficacy of LN treatment using bone marrow-derived MSCs (BM-MSCs) are still lacking.
We identified characteristics of BM-MSCs in terms of cell morphology, chromosomal stability, differentiation capacity, and phenotype through cell passages. The stability of BM-MSCs was evaluated by single-dose and repeated-dose toxicity tests, tumorigenicity tests, and biodistribution tests using lupus mouse models. Based on the encouraging nonclinical results, we conducted a nonrandomized, open-label, single-arm phase I clinical trial to evaluate the tolerability and safety of a single administration of haploidentical allogeneic BM-MSCs (CS20AT04) in seven LN patients (NCT03174587). We used a classical three + three design to find the optimal dosage. The starting dose was 2.0×10 cells/kg and escalated to 3.0×10 cells/kg if there was no dose-limiting toxicity (DLT). Evaluation of the safety and tolerability was assessed 28 days after the infusion, and the maximum tolerated dose was determined.
Properly cultured BM-MSCs showed high proliferation and multipotency, but chromosomal changes were not found. There were two deaths by a rapid administration rate in the high-dose group (2.0×10 cells/head) in a single administration test. BM-MSCs were distributed in the kidneys until Day 7. In the phase I clinical trial, seven LN patients were enrolled. Participants received BM-MSCs through intravenous infusion. There was no DLT at both initial dose (2.0×10 cells/kg) and escalated dose (3.0×10 cells/kg). One patient was not administered the full 2.0×10 cells/kg dose because of a technical error during infusion. This patient did not show DLT. Three adverse events were reported, namely, one diarrhea, one toothache, and one arthralgia, and all were considered NCI-CTC grade I events.
We defined the characteristics of BM-MSCs and identified their safety and tolerability in both animal models and a phase I clinical trial. The maximum tolerated dose was determined to be 3.0×10 cells/kg in patients with LN.
多项临床试验旨在通过引入间充质干细胞（MSCs）来治疗各种自身免疫性疾病，包括系统性红斑狼疮（SLE）。然而，对于难治性狼疮肾炎（LN），MSC 移植的结果尚不清楚，需要进一步验证。特别是，关于使用骨髓来源的间充质干细胞（BM-MSCs）治疗 LN 的安全性和有效性的数据仍然缺乏。
我们通过细胞传代鉴定了 BM-MSCs 的细胞形态、染色体稳定性、分化能力和表型特征。通过狼疮小鼠模型进行单次和重复剂量毒性试验、肿瘤形成试验和生物分布试验评估了 BM-MSCs 的稳定性。基于令人鼓舞的非临床结果，我们进行了一项非随机、开放标签、单臂 I 期临床试验，以评估 7 例 LN 患者单次给予同种异体单倍体 BM-MSCs（CS20AT04）的耐受性和安全性（NCT03174587）。我们使用经典的 3+3 设计来确定最佳剂量。起始剂量为 2.0×10^6 个细胞/kg，如果没有剂量限制性毒性（DLT），则增加至 3.0×10^6 个细胞/kg。输注后 28 天评估安全性和耐受性，确定最大耐受剂量。
适当培养的 BM-MSCs 表现出高增殖和多能性，但未发现染色体变化。单次给药试验中，高剂量组（2.0×10^6 个细胞/头）快速给药导致 2 例死亡。BM-MSCs 在肾脏中分布直到第 7 天。在 I 期临床试验中，共纳入 7 例 LN 患者。参与者通过静脉输注接受 BM-MSCs。初始剂量（2.0×10^6 个细胞/kg）和递增剂量（3.0×10^6 个细胞/kg）均无 DLT。一名患者因输注过程中的技术错误未给予全量 2.0×10^6 个细胞/kg。该患者未出现 DLT。报告了 3 例不良事件，分别为腹泻 1 例、牙痛 1 例、关节痛 1 例，均为 NCI-CTC 分级 I 事件。
我们确定了 BM-MSCs 的特征，并在动物模型和 I 期临床试验中确定了其安全性和耐受性。确定 LN 患者的最大耐受剂量为 3.0×10^6 个细胞/kg。
