Chapter IV. Clinical Trials

Immune-Directed Therapy for Type 1 Diabetes at the Clinical Level: The Immune Tolerance Network (ITN) Experience

Mario R. Ehlers¹, Gerald T. Nepom²

Manuscript submitted December 21, 2012; resubmitted January 15, 2013; accepted January 20, 2013.

Keywords: AbATE, adaptive trials, alefacept, alpha-1 antitrypsin, anti-CD3, antithymocyte globulin, autoimmunity, beta-cell, combination therapy, IL-2/rapa, immune tolerance, new onset type 1 diabetes, RETAIN, START, T1DAL

Abstract

Reestablishing immune tolerance in type 1 diabetes (T1D), a chronic autoimmune disease, is a major goal. The Immune Tolerance Network (ITN) has initiated eight clinical trials of immunomodulatory therapies in recent-onset T1D over the past decade. Results have been mixed in terms of clinical efficacy, but the studies have provided valuable mechanistic insight that are enhancing our understanding of the disease and guiding the design of future trials. Trials of non-Fc-binding anti-CD3 mAbs have revealed that modulation of this target leads to partial responses, and ITN's AbATE trial led to identification of a robust responder group that could be distinguished from non-responders by baseline metabolic and immunologic features. A pilot study of the combination of IL-2 and rapamycin gave the first demonstration that frequency and function of regulatory T cells (Tregs) can be enhanced in T1D subjects, although the therapy triggered the activation of effectors with transient β-cell dysfunction. Similarly, therapy with anti-thymocyte globulin led to substantial lymphocyte depletion, but also to the activation of the acute-phase response with no clinical benefit during preliminary analyses. These and other results provide mechanistic tools that can be used as biomarkers for safety and efficacy in future trials. Furthermore, our results, together with those of other organizations, notably TrialNet, delineate the roles of the major components of the immune response in T1D. This information is setting the stage for future combination therapy trials. The development of disease-relevant biomarkers will also enable the implementation of innovative trial designs, notably adaptive trials, which will increase efficiencies in terms of study duration and sample size, and which will expedite the conduct of trials in which there are uncertainties about dose response and effect size.

Fulltext: HTML , PDF (369KB)

This article has been cited by other articles:

	Strategies for clinical trials in type 1 diabetes Ehlers MR J Autoimmun 2016. 71:88-96
	The IL-1beta Receptor Antagonist SER140 Postpones the Onset of Diabetes in Female Nonobese Diabetic Mice Cucak H, Hansen G, Vrang N, Skarsfeldt T, Steiness E, Jelsing J J Diabetes Res 2016. 2016:7484601
	Sampling Serum in Patients With Vitiligo to Measure Disease Activity in the Skin Rashighi M, Harris JE JAMA Dermatol 2016. 152(11):1187-1188
	Multiple mechanisms involved in diabetes protection by lipopolysaccharide in non-obese diabetic mice Wang J, Cao H, Wang H, Yin G, Du J, Xia F, Lu J, Xiang M Toxicol Appl Pharmacol 2015. 285(3):149-158
	Immune-modulating effects of alpha-1 antitrypsin Ehlers MR Biol Chem 2014. 395(10):1187-1193
	Targeted immune interventions for type 1 diabetes: not as easy as it looks! Rigby MR, Ehlers MR Curr Opin Endocrinol Diabetes Obes 2014. 21(4):271-278
	Type 1 diabetes therapy beyond T cell targeting: monocytes, B cells, and innate lymphocytes Wong FS, Wen L Rev Diabet Stud 2012. 9(4):289-304