Article Figures & Data
Figures
- Figure 1 Study Design
Seven participants with rapidly progressing ALS were enrolled and underwent leukapheresis. The participants were randomized at a 1:1 ratio to active drug or placebo. Participants received IL-2 or placebo subcutaneous injections between 2 and 4 weeks before week 0. In the RCT, placebo or Treg infusions were administered every 4 weeks beginning week 0 for a total of 6 infusions. The final assessment of the RCT was performed on week 24. Six participants from the RCT entered the open-label extension (OLE). Two additional participants were directly enrolled into the OLE. All 8 participants received IL-2 beginning 2–4 weeks before the first Treg infusion. Treg infusions were administered every 4 weeks in the OLE beginning week 26 (week 0 for 2 participants who entered directly into the OLE) for a total of 6 infusions. The first 2 infusions were a 1× dose of Tregs, the next 2 infusions were a 2× dose, and the final 2 infusions were a 3× dose. The final assessment of the OLE was performed on week 50, and the final study visit occurred on week 54. IL = interleukin; RCT = randomized controlled trial; Treg = regulatory T-lymphocyte.
- Figure 2 Treg Suppressive Function and Numbers in the Randomized Controlled Trial
(A) Treg suppressive function was assessed in each participant in the placebo and Treg/IL-2 treatment groups at screening and week 24 (4 weeks after the last infusion of the RCT). (B) Treg numbers were assessed in each participant in the placebo and Treg/IL-2 treatment groups at screening and week 24 (4 weeks after the last infusion of the RCT). Data were depicted as visit-specific estimates ±standard error and were compared for progression of continuous end points using a shared-baseline, linear mixed model. A p < 0.05 was considered significant. IL = interleukin; RCT = randomized controlled trial; Treg = regulatory T-lymphocyte.
- Figure 3 Disease Progression During the RCT and OLE
(A) Four participants were randomized to the placebo group and received infusions every 4 weeks as depicted by the vertical dotted lines. Infusions #1–6 were placebo infusions in the RCT, and #7–12 were Treg infusions in the OLE. (B) Three participants were randomized to the active group (Treg/IL-2 treatment) and received infusions every 4 weeks. Infusions #1–6 were Treg infusions in the RCT, and #7–12 were Treg infusions in the OLE. Disease progression was documented in each participant by the ALSFRS-R over the duration of the 54-week study including the screening period. Placebo or IL-2 subcutaneous injections were administered beginning 2–4 weeks before the first infusion at week 0 for the RCT and 2 weeks before the 7th infusion at week 26 for the OLE. (C) Two participants were directly enrolled into the OLE and received Treg infusions every 4 weeks as depicted by the vertical dotted lines. Disease progression was documented in each participant by the ALSFRS-R over the duration of the 28-week study including the screening period. IL-2 subcutaneous injections were administered beginning 4 weeks before the first infusion at week 0. ALSFRS-R = ALS Functional Rating Scale–Revised; IL = interleukin; OLE = open-label extension; RCT = randomized controlled trial; Treg = regulatory T-lymphocyte.
- Figure 4 Treg Suppressive Function and Numbers in the Open-Label Extension (OLE)
(A) Treg suppressive function was assessed in each participant at screening, 4 weeks after the second infusion of a 1× dose of Tregs (week 34), 4 weeks after the second infusion of a 2× dose (week 42), and 4 weeks after the second infusion of a 3× dose (week 50). (B) Treg numbers were assessed in each participant at screening, 4 weeks after the second infusion of a 1× dose of Tregs (week 34), 4 weeks after the second infusion of a 2× dose (week 42), and 4 weeks after the second infusion of the 3× dose (week 50). Data were depicted as visit-specific estimates ±standard error and were compared for progression of continuous end points using a shared-baseline, linear mixed model. A p < 0.05 was considered significant. Treg = regulatory T-lymphocyte.
- Figure 5 Disease Progression of Participants During the Open-Label Extension (OLE)
Disease progression was documented in each participant by the ALSFRS-R over the duration of the 24-week OLE. The timing of the Treg infusions was depicted by the vertical dotted lines with the corresponding Treg dosages. The baseline ALSFRS-R value for the OLE was taken at week 26 for the 6 participants who went through the RCT and week 0 for the 2 participants who entered directly into the OLE. The total change in the ALSFRS-R was calculated after 24 weeks. Six of the 8 participants showed intermediate to no progression of the ALSFRS-R (average of −2.7 points). Two of the 8 participants showed rapid progression (average of −10.5 points). ALSFRS-R = ALS Functional Rating Scale–Revised; Treg = regulatory T-lymphocyte.
- Figure 6 Peripheral Markers of Inflammation and Oxidative Stress During the Open-Label Extension (OLE)
Sera from all 8 participants were collected during the OLE and assayed through an Olink proteomic study for markers of inflammation and oxidative stress. Two markers of inflammation, (A) IL-17F and (B) IL-17C, were higher in the 2 participants who progressed rapidly during the OLE compared with the 6 participants who showed intermediate to no progression. One marker of oxidative stress, (C) oxidized low-density lipoprotein receptor 1 (OLR1), was elevated in the 2 rapidly progressing participants compared with the other 6 participants. An ELISA for another marker of oxidative stress, (D) oxidized low-density lipoprotein (ox-LDL), showed higher levels in the 2 rapidly progressing participants compared with the other 6 participants. Levels of IL-17F, IL-17C, and OLR1 in sera from 9 healthy controls were depicted as shaded areas of the mean ± SD. Levels of ox-LDL in sera from 26 healthy controls were depicted as a shaded area of the mean ± SD. The levels of ox-LDL in the participants were standardized to the control levels. These data were not statistically analyzed as there were only 2 participants in the rapidly progressive group. IL = interleukin.
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