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

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 betweengroup 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.FUNDING. NIH and Astellas.

Exercise to preserve β‐cell function in recent‐onset Type 1 diabetes mellitus (EXTOD) – a randomized controlled pilot trial

“…The dropout rate of 29% in this study is about twice that originally predicted in the study design, and described in studies of immunotherapeutic agents for new-onset Type 1 diabetes [34]. Our previous study of exercise intervention in people with newly diagnosed Type 2 diabetes only reported a 3% dropout rate [9].…”

Regulatory T cell therapy for type 1 diabetes: May the force be with you

“…Treated subjects had an increase in Treg function and IL-10 production, with a selective decrease in the pro-inflammatory cytokine IFN-g. Murine studies indicate that the anti-CD3 mAb selectively depletes Teffs while preserving Tregs [47]. Promising findings were also noted in the TIDAL study, in which new onset T1D subjects treated with human leukocyte function antigen-3 (LFA-3)-Ig (Alefacept) exhibited depletion of T central and effector memory cells but preserved Tregs, with an increase in the Treg to Teff ratio, and with resultant preservation of beta cell function approximately 18 months after therapy was stopped [12]. Although anti-thymocyte globulin (ATG) alone was ineffective [48], lower dose ATG coupled with granulocyte colony stimulating factor (GCSF) appears promising in resetting the balance bewteen Tregs and Teffs in recent onset T1D, while preserving beta cell function [49].…”

“…We posit that one successful approach would be to augment the Treg pool with an ex vivo expanded Treg infusion, while debulking the Teff population with drugs such as anti-CD3 monoclonal antibody or LFA3-Ig, which have already shown some promise in new onset T1D trials [11,12].…”

Restoring Regulatory T Cells in Type 1 Diabetes

“…On the other hand, Alefacept is a LFA-3Ig fusion protein that binds to CD2 on T cells with much lower affinity [115]. When used in a multicenter clinical trial in T1D, alefacept treatment resulted in selective depletion of memory T cells while preserving naïve T cells and Tregs [116]. Alefacept treatment also showed promising efficacy in improving metabolic outcomes in T1D patients, including C-peptide preservation, lower insulin use, and reduction in hypoglycemic events [117].…”