Clinical Safety and Preliminary Efficacy of Regulatory T Cells for ALS

Peripheral and neuroinflammation have been previously associated with progression in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease involving progressive loss of motor neurons. We hypothesize that regulatory T cell (Treg) therapy can resolve inflammation and preserve function in those patients with ALS. Participants with ALS received infusions of a fixed dose (100×106 cells) of umbilical cord blood-derived, allogeneic, nonhuman leukocyte antigen-matched, cryopreserved Treg product (TREG), administered as four weekly infusions followed by six monthly infusions. No lymphodepletion, immunosuppression, or interleukin 2 was administered. The primary outcome was dose-limiting toxicity, including infusion reaction within 24 hours (as graded by National Cancer Institute - Common Terminology Criteria for Adverse Events, Version 4.0) and/or regimen-related death, or grade 3 or 4 cytokine release syndrome within 14 days postinfusion. We measured clinical response using the Revised ALS Functional Rating Scale (ALSFRS-R; range 0 to 48, with lower numbers indicating lower functional ability). Exploratory analyses measured serum and plasma neurofilament light (NfL) and inflammatory biomarkers. Six participants with a median age of 48.5 years (range 27 to 66 years) and baseline ALSFRS-R score of 31.5 (range 23 to 43) were treated with a median of 11 (range 6 to 22) TREG infusions in an ambulatory setting. No dose-limiting toxicity was observed. In participants with sufficient data points (n=4), the mean ALSFRS-R slope of decline was -1.66±1.03 points/month before treatment, -0.41±0.45/month during treatment, and -0.60±0.59/month posttreatment. Biomarkers including NfL and inflammatory markers MIP-1δ (macrophage inflammatory protein-1 delta), CTACK (cutaneous T cell-attracting chemokine), and GROα (growth-regulated oncogene alpha) exhibited different relationships with ALSFRS-R score between participants. This study demonstrates the preliminary safety of "off-the-shelf", allogeneic Treg-cell therapy.