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

• Authors: Mark R. Rigby, Indiana University School of Medicine; Kristina M. Harris, Immune Tolerance Network; Ashley Pinckney, Rho Inc.; Linda A. DiMeglio, Indiana University School of Medicine; Marc S. Rendell, Creighton Diabetes Center; Eric Felner, Emory University; Jean M. Dostou, University of North Carolina School of Medicine at Chapel Hill; Stephen E. Gitelman, UCSF; Kurt J. Griffin, University of Arizona; Eva Tsalikian, University of Iowa; Peter A. Gottlieb, University of Colorado School of Medicine; Carla J. Greenbaum, Benaroya Research Institute at Virginia Mason; Nicole A. Sherry, Massachusetts General Hospital; Wayne V. Moore, University of Missouri; Roshanak Monzavi, USC Keck School of Medicine; Steven M. Willi, Children’s Hospital of Philadelphia; Philip Raskin, The University of Texas Southwestern Medical Center; Lynette Keyes-Elstein, Rho Inc.; S. Alice Long, Benaroya Research Institute at Virginia Mason; Sai Kanaparthi, Immune Tolerance Network; Noha Lim, Immune Tolerance Network; Deborah Phippard, Immune Tolerance Network; Carol L. Soppe, Immune Tolerance Network; Margret L. Fitzgibbon, National Institutes of Allergy and Infectious Diseases; James McNamara, National Institutes of Allergy and Infectious Diseases; Gerald T. Nepom, Benaroya Research Institute at Virginia Mason; Mario R. Ehlers, Immune Tolerance Network; T1DAL Study Group, Immune Tolerance Network
• Journal Title: Journal of Clinical Investigation
• Volume: Volume 125, Number 8
• Publisher: AMER SOC CLINICAL INVESTIGATION INC | 2015-08-01, Pages 3285-3296
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1172/JCI81722
• Subjects: Health Sciences, General; Health Sciences, Immunology; Health Sciences, Medicine and Surgery
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; BETA-CELL FUNCTION; ANTI-CD3 MONOCLONAL-ANTIBODY; C-PEPTIDE RESPONSES; MEMORY T-CELLS; DOUBLE-BLIND; NOD MICE; CONTROLLED-TRIAL; PHASE-2 TRIAL; PD-1 PATHWAY; PSORIASIS

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.