Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons With Amyotrophic Lateral Sclerosis

Jason R. Thonhoff, James D. Berry, Eric A. Macklin, David R. Beers, Patricia A. Mendoza, Weihua Zhao, Aaron D. Thome, Fabio Triolo, James J. Moon, Sabrina Paganoni, Merit Cudkowicz, Stanley H. Appel

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Background and Objective s : 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 × 106 cells/kg) IV every 4 weeks and IL-2 (2 × 105 IU/m2) 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 × 106 cells/kg and 3 × 106 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 ( 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.

Original languageEnglish (US)
Article numbere200019
JournalNeurology: Neuroimmunology and NeuroInflammation
Issue number6
StatePublished - Nov 29 2022


  • Amyotrophic Lateral Sclerosis/drug therapy
  • Biomarkers
  • Disease Progression
  • Humans
  • Inflammation
  • Interleukin-2/adverse effects
  • T-Lymphocytes, Regulatory
  • COVID-19 Drug Treatment

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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