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Combined Regulatory T-Lymphocyte and IL-2 Treatment Is Safe, Tolerable, and Biologically Active for 1 Year in Persons
Jason R Thonhoff1, James D Berry1, Eric A Macklin1
1From 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.
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 × 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 (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.
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