Résumé
Background:Low-dose interleukin-2 (ld-IL-2) enhances regulatory T-cell (Treg) function in auto-inflamma-tory conditions. Neuroinflammation being a pathogenic feature of amyotrophic lateral sclerosis (ALS), weevaluated the pharmacodynamics and safety of ld-IL-2 in ALS subjects.Methods:We performed a single centre, parallel three-arm, randomised, double-blind, placebo-controlledstudy. Eligibility criteria included age<75 years, disease duration<5 years, riluzole treatment>3 months,and a slow vital capacity70% of normal. Patients were randomised (1:1:1) to aldesleukin 2 MIU, 1 MIU, orplacebo once daily for 5 days every 4 weeks for 3 cycles. Primary outcome was change from baseline in Tregpercentage of CD4+T cells (%Tregs) following afirst cycle. Secondary laboratory outcomes included: %Tregand Treg number following repeated cycles, and plasma CCL2 and neurofilament light chain protein (NFL)concentrations as surrogate markers of efficacy. Safety outcomes included motor-function (ALSFRS-R), slowvital capacity (SVC), and adverse event reports. This trial is registered with ClinicalTrials.gov, NCT02059759.Findings:All randomised patients (12 per group), recruited from October 2015 to December 2015, were aliveat the end of follow-up and included in the intent-to-treat (ITT) analysis. No drug-related serious adverseevent was observed. Non-serious adverse events occurred more frequently with the 1 and 2 MIU IL-2 dosescompared to placebo, including injection site reactions andflu-like symptoms. Primary outcome analysisshowed a significant increase (p<0¢0001) in %Tregs in the 2 MIU and 1 MIU arms (mean [SD]: 2 MIU: +6¢2%[2¢2]; 1 MIU: +3¢9% [1¢2]) as compared to placebo (mean [SD]: -0¢49% [1¢3]). Effect sizes (ES) were large intreated groups: 2 MIU ES=3¢7 (IC95%: 2¢34¢9) and 1 MIU ES=3¢5 (IC95%: 2¢14¢6). Secondary outcomesshowed a significant increase in %Tregs following repeated cycles (p<0¢0001) as compared to placebo, and adose-dependent decrease in plasma CCL2 (p=0¢0049). There were no significant differences amongst thethree groups on plasma NFL levels.Interpretation:Ld-IL-2 is well tolerated and immunologically effective in subjects with ALS. These results war-rant further investigation into their eventual therapeutic impact on slowing ALS disease progression.Funding:: The French Health Ministry (PHRC-I-14-056), EU H2020 (grant #633413), and the Association pourla Recherche sur la SLA (ARSLA)