Department of Neurology, Medical University of Gdańsk, Debinki 7, 80-210, Gdańsk, Poland.
Department of Anaesthesiology and Intensive Care, Medical University of Gdańsk, Debinki 7, 80-210 Gdańsk, Poland.
BioDrugs. 2021 Jan;35(1):47-60. doi: 10.1007/s40259-020-00462-7. Epub 2021 Jan 5.
Multiple sclerosis (MS) is an immune-mediated disease in which autoimmune T conventional (T) cells break the blood-brain barrier and destroy neurons of the central nervous system. It is hypothesized that CD4CD25CD127FoxP3 T regulatory (T) cells may inhibit this destruction through suppressive activity exerted on T cells.
We present the results of a phase 1b/2a, open-label, two-arm clinical trial in 14 patients treated with autologous T cells for relapsing-remitting MS. The patients received either expanded ex vivo T cells intravenously (intravenous [IV] group, n = 11; dose 40 × 10 T cells/kg of body weight) or freshly isolated T cells intrathecally (intrathecal [IT] group, n = 3; dose 1.0 × 10 T cells). Importantly, patients were not treated with any other disease-modifying drugs for at least 6 months before the recruitment and during the follow-up.
No severe adverse events were observed. Self-assessed quality of life (EuroQol-5 Dimensions [EQ-5D] form) did not change and did not differ significantly between the groups. A total of 12 relapses were noted in five intravenously treated patients, who had from one to three attacks per year. Three out of ten participants who completed the trial in the IV group deteriorated more than 1 point on the Expanded Disability Status Scale (EDSS) during the follow-up. At the same time, no patients in the IT group experienced a relapse or such a deterioration in the EDSS. No significant differences were found in the Multiple Sclerosis Functional Composite (MSFC) scale in both the IV and IT groups. Magnetic resonance imaging (MRI) scans revealed a significantly lower change in the T2 lesion volume in the IT group compared to the IV group. The increase in the number of new T2 lesions during the follow-up was significant for the IV group only. There were no significant changes in the level of T cells or T cells in the peripheral blood throughout the follow-up or between the groups. Interestingly, T cells in all patients consisted of two different phenotypes: peripheral T cells Helios(-) (≈ 20%) and thymic T cells Helios(+) (≈ 80%). The analysis of the cytokine pattern revealed higher levels of transforming growth factor-α and proinflammatory factors MCP3, CXCL8, and IL-1RA in the IT group compared with the IV group.
No serious adverse events were reported in the 14 patients with MS treated with T cells in this study. The results suggest that IT administration is more promising than IV administration. Because of the low number of patients recruited, the statistical results may be underpowered and further studies are necessary to reach conclusions on efficacy and safety.
EudraCT: 2014-004320-22; registered 18 November 2014.
多发性硬化症（MS）是一种免疫介导的疾病，其中自身免疫性 T 常规（T）细胞破坏血脑屏障并破坏中枢神经系统的神经元。据推测，CD4CD25CD127FoxP3 T 调节（T）细胞可能通过对 T 细胞发挥抑制活性来抑制这种破坏。
我们介绍了 14 例复发性缓解型多发性硬化症患者接受自体 T 细胞治疗的 1b/2a 期、开放标签、双臂临床试验的结果。患者接受了静脉内（静脉内[IV]组，n=11；剂量 40×10 T 细胞/kg 体重）或鞘内（鞘内[IT]组，n=3；剂量 1.0×10 T 细胞）体外扩增的 T 细胞。重要的是，在招募和随访期间，患者至少在 6 个月内未接受任何其他疾病修正药物治疗。
未观察到严重不良事件。自我评估的生活质量（EuroQol-5 维度[EQ-5D]表格）没有变化，两组之间也没有显著差异。五名接受静脉内治疗的患者共出现 12 次复发，每年有一至三次发作。在 IV 组完成试验的十名参与者中有三名在随访期间扩展残疾状态量表（EDSS）恶化超过 1 分。与此同时，IT 组没有患者出现复发或 EDSS 恶化。在 IV 和 IT 组中，多发性硬化功能综合（MSFC）量表均未发现显著差异。磁共振成像（MRI）扫描显示，与 IV 组相比，IT 组的 T2 病变体积变化明显较低。仅在 IV 组中，随访期间新 T2 病变数量的增加具有统计学意义。整个随访期间或两组之间，T 细胞或外周血中的 T 细胞水平均无明显变化。有趣的是，所有患者的 T 细胞都由两种不同的表型组成：外周 T 细胞 Helios(-)（≈20%）和胸腺 T 细胞 Helios(+)（≈80%）。细胞因子模式分析显示，与 IV 组相比，IT 组转化生长因子-α和促炎因子 MCP3、CXCL8 和 IL-1RA 水平更高。
在本研究中，14 名接受 T 细胞治疗的 MS 患者未报告严重不良事件。结果表明，IT 给药比 IV 给药更有前途。由于招募的患者数量较少，统计结果可能效力不足，需要进一步研究才能得出疗效和安全性的结论。
EudraCT：2014-004320-22；注册于 2014 年 11 月 18 日。
