Abstract
Background and objectives: 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.
Methods: 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 6 cells/kg) IV every 4 weeks and IL-2 (2 × 10 5 IU/m 2 ) 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 6 cells/kg and 3 × 10 6 cells/kg at 4-week intervals.
Results: 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.
Discussion: 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 ).
Classification of evidence: This study provides Class IV evidence that Treg infusions and IL-2 injections are safe and effective for patients with ALS.
【초록키워드】 Randomized controlled trial, Treatment, Inflammation, therapy, Open-label, reliability, COVID-19 pandemic, progression, classification, oxidative stress, RCT, Regulatory, Disease progression, Practice, Patient, Placebo, Leukapheresis, receptor, group, Treg, IL-2, marker, LDL, clinical study, Evidence, Safe, Tregs, T-lymphocyte, average, help, injection, participant, Dose escalation, class, low-density, doses, extension, intervals, matching placebo, Good, ALS, effective, autologous, Randomly, dose-escalation, enrolled, elevated, conducted, provide, changed, assigned, oxidized, receive, 1:1, baseline, slow disease, suppressive function, 【제목키워드】 IL-2, T-lymphocyte, Lateral Sclerosis, Combined, Person, Year,