Immune-Directed Therapy for Type 1 Diabetes at the Clinical Level: 2012 Update on the Immune Tolerance Network (ITN) Experience
Mario R. Ehlers1 and Gerald T. Nepom2
1 Clinical Trials Group, Immune Tolerance Network, 185 Berry Street, Suite 3515, San Francisco, CA 94107, USA
2 Benaroya Research Institute, 1201 9th Avenue Seattle, WA 9810, USA
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 insights that are enhancing our understanding of the disease and are guiding the design of future trials. Trials of non-Fc-binding anti-CD3 mAb have revealed that modulation of the T cell 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 Treg cells can be enhanced in T1D subjects, although the therapy also triggered activation of effectors with transient β-cell dysfunction. Similarly, therapy with anti-thymocyte globulin led to substantial lymphocyte depletion, but also activation of the acute phase response with no clinical benefit during preliminary analyses. These and other results are providing 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, are delineating the roles of the major components of the immune response in T1D. They are 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.
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