Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

Immune Tolerance Network (ITN) T1DAL Study Group

Research output: Contribution to journalArticle

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Abstract

BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4<sup>+</sup> and CD8<sup>+</sup> central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1<sup>+</sup>CD4<sup>+</sup> Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458.

Original languageEnglish
Pages (from-to)3285-3296
Number of pages12
JournalJournal of Clinical Investigation
Volume125
Issue number8
DOIs
StatePublished - Aug 3 2015

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Type 1 Diabetes Mellitus
C-Peptide
Hypoglycemic Agents
Insulin
T-Lymphocytes
Area Under Curve
Placebos
Meals
Control Groups
alefacept
Therapeutics
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

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Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. / Immune Tolerance Network (ITN) T1DAL Study Group.

In: Journal of Clinical Investigation, Vol. 125, No. 8, 03.08.2015, p. 3285-3296.

Research output: Contribution to journalArticle

Immune Tolerance Network (ITN) T1DAL Study Group. / Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 8. pp. 3285-3296.
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abstract = "BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50{\%} reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458.",
author = "{Immune Tolerance Network (ITN) T1DAL Study Group} and Rigby, {Mark R.} and Harris, {Kristina M.} and Ashley Pinckney and Linda DiMeglio and Rendell, {Marc S.} and Felner, {Eric I.} and Dostou, {Jean M.} and Gitelman, {Stephen E.} and Griffin, {Kurt J.} and Eva Tsalikian and Gottlieb, {Peter A.} and Greenbaum, {Carla J.} and Sherry, {Nicole A.} and Moore, {Wayne V.} and Roshanak Monzavi and Willi, {Steven M.} and Philip Raskin and Lynette Keyes-Elstein and Long, {S. Alice} and Sai Kanaparthi and Noha Lim and Deborah Phippard and Soppe, {Carol L.} and Fitzgibbon, {Margret L.} and James McNamara and Nepom, {Gerald T.} and Ehlers, {Mario R.}",
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T1 - Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients

AU - Immune Tolerance Network (ITN) T1DAL Study Group

AU - Rigby, Mark R.

AU - Harris, Kristina M.

AU - Pinckney, Ashley

AU - DiMeglio, Linda

AU - Rendell, Marc S.

AU - Felner, Eric I.

AU - Dostou, Jean M.

AU - Gitelman, Stephen E.

AU - Griffin, Kurt J.

AU - Tsalikian, Eva

AU - Gottlieb, Peter A.

AU - Greenbaum, Carla J.

AU - Sherry, Nicole A.

AU - Moore, Wayne V.

AU - Monzavi, Roshanak

AU - Willi, Steven M.

AU - Raskin, Philip

AU - Keyes-Elstein, Lynette

AU - Long, S. Alice

AU - Kanaparthi, Sai

AU - Lim, Noha

AU - Phippard, Deborah

AU - Soppe, Carol L.

AU - Fitzgibbon, Margret L.

AU - McNamara, James

AU - Nepom, Gerald T.

AU - Ehlers, Mario R.

PY - 2015/8/3

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N2 - BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458.

AB - BACKGROUND. Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS. In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS. A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS. In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION. https://clinicaltrials.gov/ NCT00965458.

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