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

• Type of Material: Article
• 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
• Language: English
• Date: 2015-08-01
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: Copyright © 2015, American Society for Clinical Investigation
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI81722
• Title of Journal or Parent Work: Journal of Clinical Investigation
• Volume: 125
• Issue: 8
• Start Page: 3285
• End Page: 3296
• Grant/Funding Information: The trial was conducted by the ITN and sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) under Award Numbers NO1-AI-15416 and UM1AI109565.; Additional funding was provided by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).; Bayer HealthCare LLC, Diabetes Care provided blood glucose monitoring supplies through an investigator-sponsored research grant.; This project was in part supported, at Indiana University, by the Indiana Clinical and Translational Sciences Institute, funded in part by Grant Number TR000006 from the NIH, National Center for Advancing Translational Sciences (NCATS), Clinical and Translational Sciences Award; at UCSF, by Grant Numbers UL1 RR024131 and UL1 TR000004 from the National Center for Research Resources (NCRR) and the NCATS, NIH; at CHOP, by Grants UL1RR024134 and UL1TR000003 from the NCRR and the NCATS.
• Keywords: NOD MICE; DOUBLE-BLIND; Science & Technology; PSORIASIS; PHASE-2 TRIAL; ANTI-CD3 MONOCLONAL-ANTIBODY; Life Sciences & Biomedicine; Research & Experimental Medicine; BETA-CELL FUNCTION; CONTROLLED-TRIAL; C-PEPTIDE RESPONSES; MEMORY T-CELLS; PD-1 PATHWAY; Medicine, Research & Experimental
• Research Categories: Health Sciences, General; Health Sciences, Immunology; Health Sciences, Medicine and Surgery

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.