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November 2022; 9 (6) Research ArticleOpen Access

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
First published August 29, 2022, DOI: https://doi.org/10.1212/NXI.0000000000200019
Jason R. Thonhoff
From 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.
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James D. Berry
From 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.
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Eric A. Macklin
From 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.
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David R. Beers
From 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.
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Patricia A. Mendoza
From 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.
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Weihua Zhao
From 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.
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Aaron D. Thome
From 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.
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Fabio Triolo
From 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.
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James J. Moon
From 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.
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Sabrina Paganoni
From 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.
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Merit Cudkowicz
From 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.
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Stanley H. Appel
From 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.
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Full PDF
Citation
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
Neurol Neuroimmunol Neuroinflamm Nov 2022, 9 (6) e200019; DOI: 10.1212/NXI.0000000000200019

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    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.

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    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.

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    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.

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    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.

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    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.

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    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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