Summary
Background Type 1 diabetes (T1D) results from loss of immune regulation leading to the development of autoimmunity to pancreatic beta-cells, involving autoreactive T effector cells (Teffs). Regulatory T cells (Tregs), that prevent autoimmunity, require Interleukin-2 (IL-2) for maintenance of immunosuppressive functions and, alterations in the IL-2 pathway predispose to T1D. Using an adaptive trial design we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of autoreactive Teffs.
Methods DILfrequency is a single-center, non-randomised, open-label, response-adaptive study of participants aged 18 to 70 years with T1D. The initial learning phase allocated 12 participants to six different predefined dose-frequency regimens. Then, three cohorts of 8 participants were sequentially allocated dose-frequencies, based on repeated interim analyses of all accumulated trial data. The co-primary endpoints were percentage change in Tregs, Teffs and, CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. Trial registration ISRCTN40319192 and ClinicalTrials.gov (NCT02265809).
Findings 115 participants were assessed between November 17th 2014 and May 22nd 2016, 38 participants were enrolled with 36 completing treatment. The optimal regimen to maintain a steady state increase in Tregs of 30% and CD25 expression of 25% without Teff expansion is 0.26 × 106 IU/m2 (95% CI (−0.007 to 0.485)) every 3 days (1.3 to 4.4). Tregs and CD25 were dose-frequency responsive, while Teffs were not. The commonest adverse event was injection site reaction (464/694 events), with a single participant developing transient eosinophilia at the highest dose (0.47 × 106 IU/m2).
Interpretation This response-adaptive trial defined a well-tolerated aldesleukin regimen that specifically induces Treg expansion that can now be trialled to treat T1D.
Funding Sir Jules Thorn Trust, Wellcome, JDRF, SNSF, NIHR
