From the Houston Methodist Neurological Institute (J.R.T., D.R.B., P.A.M., W.Z., A.D.T., S.H.A.), Houston Methodist Hospital Research Institute, Stanley H. Appel Department of Neurology, Houston, TX; Neurological Clinical Research Institute (J.D.B., S.P., M.C.), Healey & AMG Center for ALS, Massachusetts General Hospital, Boston, MA; Biostatistics Center (E.A.M.), Massachusetts General Hospital, Boston, MA; Harvard Medical School (E.A.M.), Boston, MA; Department of Pediatric Surgery (F.T.), McGovern Medical School, UTHealth-The University of Texas Health Science Center at Houston, Houston, TX; and Center for Immunology and Inflammatory Diseases (J.J.M.), Massachusetts General Hospital, Boston, MA; and Harvard Medical School (J.J.M.), Boston, MA.
Neurol Neuroimmunol Neuroinflamm. 2022 Aug 29;9(6). doi: 10.1212/NXI.0000000000200019. Print 2022 Nov.
In a phase 1 amyotrophic lateral sclerosis (ALS) study, autologous infusions of expanded regulatory T-lymphocytes (Tregs) combined with subcutaneous interleukin (IL)-2 were safe and well tolerated. Treg suppressive function increased and disease progression stabilized during the study. The present study was conducted to confirm the reliability of these results.
Participants with ALS underwent leukapheresis, and their Tregs were isolated and expanded in a current Good Manufacturing Practice facility. Seven participants were randomly assigned in a 1:1 ratio to receive Treg infusions (1 × 10 cells/kg) IV every 4 weeks and IL-2 (2 × 10 IU/m) injections 3 times/wk or matching placebo in a 24-week randomized controlled trial (RCT). Six participants proceeded into a 24-week dose-escalation open-label extension (OLE). Two additional participants entered directly into the OLE. The OLE included dose escalation of Treg infusions to 2 × 10 cells/kg and 3 × 10 cells/kg at 4-week intervals.
The Treg/IL-2 treatments were safe and well tolerated, and Treg suppressive function was higher in the active group of the RCT. A meaningful evaluation of progression rates in the RCT between the placebo and active groups was not possible due to the limited number of enrolled participants aggravated by the COVID-19 pandemic. In the 24-week OLE, the Treg/IL-2 treatments were also safe and well tolerated in 8 participants who completed the escalating doses. Treg suppressive function and numbers were increased compared with baseline. Six of 8 participants changed by an average of -2.7 points per the ALS Functional Rating Scale-Revised, whereas the other 2 changed by an average of -10.5 points. Elevated levels of 2 markers of peripheral inflammation (IL-17C and IL-17F) and 2 markers of oxidative stress (oxidized low-density lipoprotein receptor 1 and oxidized LDL) were present in the 2 rapidly progressing participants but not in the slower progressing group.
Treg/IL-2 treatments were safe and well tolerated in the RCT and OLE with higher Treg suppressive function. During the OLE, 6 of 8 participants showed slow to no progression. The 2 of 8 rapid progressors had elevated markers of oxidative stress and inflammation, which may help delineate responsiveness to therapy. Whether Treg/IL-2 treatments can slow disease progression requires a larger clinical study (ClinicalTrials.gov number, NCT04055623).
This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.
在一项针对肌萎缩侧索硬化症（ALS）的 1 期研究中，自体扩增的调节性 T 淋巴细胞（Tregs）输注联合皮下白细胞介素（IL）-2 治疗是安全且耐受良好的。在研究过程中，Treg 的抑制功能增加，疾病进展稳定。本研究旨在证实这些结果的可靠性。
ALS 患者接受白细胞分离术，其 Treg 在符合现行良好生产规范的设施中进行分离和扩增。将 7 名参与者随机按 1:1 的比例分配，接受 Treg 输注（1×10 个细胞/kg），每 4 周静脉注射一次，同时每周皮下注射 3 次白细胞介素（IL）-2（2×10 IU/m），或在 24 周随机对照试验（RCT）中接受匹配的安慰剂。6 名参与者继续进行 24 周的剂量递增开放标签扩展（OLE）。另外 2 名参与者直接进入 OLE。OLE 包括在 4 周间隔内将 Treg 输注剂量递增至 2×10 个细胞/kg 和 3×10 个细胞/kg。
Treg/IL-2 治疗是安全且耐受良好的，并且在 RCT 的活性组中，Treg 的抑制功能更高。由于 COVID-19 大流行加剧了参与者人数有限的问题，因此在 RCT 中对安慰剂和活性组之间的进展率进行有意义的评估是不可能的。在 24 周的 OLE 中，8 名完成递增剂量的参与者也耐受了 Treg/IL-2 治疗，并且安全无不良反应。与基线相比，Treg 的抑制功能和数量均增加。8 名参与者中有 6 名按 ALS 功能评定量表修订版平均降低了-2.7 分，而另外 2 名平均降低了-10.5 分。在 2 名进展迅速的参与者中存在 2 种外周炎症标志物（IL-17C 和 IL-17F）和 2 种氧化应激标志物（氧化型低密度脂蛋白受体 1 和氧化型 LDL）的升高，但在进展较慢的组中未发现。
在 RCT 和 OLE 中，Treg/IL-2 治疗是安全且耐受良好的，同时 Treg 的抑制功能更高。在 OLE 期间，8 名参与者中有 6 名进展缓慢或无进展。8 名快速进展者中有 2 名存在氧化应激和炎症标志物升高，这可能有助于确定对治疗的反应。Treg/IL-2 治疗是否能减缓疾病进展还需要更大规模的临床研究（ClinicalTrials.gov 注册号：NCT04055623）。
本研究提供了 IV 级证据，表明 Treg 输注和白细胞介素-2 注射对 ALS 患者是安全有效的。
