Dataset Information

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

ABSTRACT:

Background

Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant human IL-2), which is administered at high doses to activate the immune system in cancer immunotherapy, is now being repositioned to treat inflammatory and autoimmune disorders at lower doses by targeting Tregs.

Methods and findings

To define the aldesleukin dose response for Tregs and to find doses that increase Tregs physiologically for treatment of T1D, a statistical and systematic approach was taken by analysing the pharmacokinetics and pharmacodynamics of single doses of subcutaneous aldesleukin in the Adaptive Study of IL-2 Dose on Regulatory T Cells in Type 1 Diabetes (DILT1D), a single centre, non-randomised, open label, adaptive dose-finding trial with 40 adult participants with recently diagnosed T1D. The primary endpoint was the maximum percentage increase in Tregs (defined as CD3+CD4+CD25highCD127low) from the baseline frequency in each participant measured over the 7 d following treatment. There was an initial learning phase with five pairs of participants, each pair receiving one of five pre-assigned single doses from 0.04 × 106 to 1.5 × 106 IU/m2, in order to model the dose-response curve. Results from each participant were then incorporated into interim statistical modelling to target the two doses most likely to induce 10% and 20% increases in Treg frequencies. Primary analysis of the evaluable population (n = 39) found that the optimal doses of aldesleukin to induce 10% and 20% increases in Tregs were 0.101 × 106 IU/m2 (standard error [SE] = 0.078, 95% CI = -0.052, 0.254) and 0.497 × 106 IU/m2 (SE = 0.092, 95% CI = 0.316, 0.678), respectively. On analysis of secondary outcomes, using a highly sensitive IL-2 assay, the observed plasma concentrations of the drug at 90 min exceeded the hypothetical Treg-specific therapeutic window determined in vitro (0.015-0.24 IU/ml), even at the lowest doses (0.040 × 106 and 0.045 × 106 IU/m2) administered. A rapid decrease in Treg frequency in the circulation was observed at 90 min and at day 1, which was dose dependent (mean decrease 11.6%, SE = 2.3%, range 10.0%-48.2%, n = 37), rebounding at day 2 and increasing to frequencies above baseline over 7 d. Teffs, natural killer cells, and eosinophils also responded, with their frequencies rapidly and dose-dependently decreased in the blood, then returning to, or exceeding, pretreatment levels. Furthermore, there was a dose-dependent down modulation of one of the two signalling subunits of the IL-2 receptor, the ? chain (CD122) (mean decrease = 58.0%, SE = 2.8%, range 9.8%-85.5%, n = 33), on Tregs and a reduction in their sensitivity to aldesleukin at 90 min and day 1 and 2 post-treatment. Due to blood volume requirements as well as ethical and practical considerations, the study was limited to adults and to analysis of peripheral blood only.

Conclusions

The DILT1D trial results, most notably the early altered trafficking and desensitisation of Tregs induced by a single ultra-low dose of aldesleukin that resolves within 2-3 d, inform the design of the next trial to determine a repeat dosing regimen aimed at establishing a steady-state Treg frequency increase of 20%-50%, with the eventual goal of preventing T1D.

Trial registration

ISRCTN Registry ISRCTN27852285; ClinicalTrials.gov NCT01827735.

SUBMITTER: Todd JA

PROVIDER: S-EPMC5058548 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

Todd John A JA Evangelou Marina M Cutler Antony J AJ Pekalski Marcin L ML Walker Neil M NM Stevens Helen E HE Porter Linsey L Smyth Deborah J DJ Rainbow Daniel B DB Ferreira Ricardo C RC Esposito Laura L Hunter Kara M D KM Loudon Kevin K Irons Kathryn K Yang Jennie H JH Bell Charles J M CJ Schuilenburg Helen H Heywood James J Challis Ben B Neupane Sankalpa S Clarke Pamela P Coleman Gillian G Dawson Sarah S Goymer Donna D Anselmiova Katerina K Kennet Jane J Brown Judy J Caddy Sarah L SL Lu Jia J Greatorex Jane J Goodfellow Ian I Wallace Chris C Tree Tim I TI Evans Mark M Mander Adrian P AP Bond Simon S Wicker Linda S LS Waldron-Lynch Frank F

PLoS medicine 20161011 10

<h4>Background</h4>Interleukin-2 (IL-2) has an essential role in the expansion and function of CD4+ regulatory T cells (Tregs). Tregs reduce tissue damage by limiting the immune response following infection and regulate autoreactive CD4+ effector T cells (Teffs) to prevent autoimmune diseases, such as type 1 diabetes (T1D). Genetic susceptibility to T1D causes alterations in the IL-2 pathway, a finding that supports Tregs as a cellular therapeutic target. Aldesleukin (Proleukin; recombinant huma ...[more]

PMID: 27727279

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Project description:IntroductionCD4 T regulatory cells (Tregs) are crucial for the maintenance of self-tolerance and are deficient in many common autoimmune diseases such as type 1 diabetes (T1D). Interleukin 2 (IL-2) plays a major role in the activation and function of Tregs and treatment with ultra-low dose (ULD) IL-2 could increase Treg function to potentially halt disease progression in T1D. However, prior to embarking on large phase II/III clinical trials it is critical to develop new strategies for determining the mechanism of action of ULD IL-2 in participants with T1D. In this mechanistic study we will combine a novel trial design with a clinical grade Treg assay to identify the best doses of ULD IL-2 to induce targeted increases in Tregs.Method and analysisAdaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D) is a single centre non-randomised, single dose, open label, adaptive dose-finding trial. The primary objective of DILT1D is to identify the best doses of IL-2 to achieve a minimal or maximal Treg increase in participants with T1D (N=40). The design has an initial learning phase where pairs of participants are assigned to five preassigned doses followed by an interim analysis to determine the two Treg targets for the reminder of the trial. This will then be followed by an adaptive phase which is fully sequential with an interim analysis after each participant is observed to determine the choice of dose based on the optimality criterion to minimise the determinant of covariance of the estimated target doses. A dose determining committee will review all data available at the interim(s) and then provide decisions regarding the choice of dose to administer to subsequent participants.Ethics and disseminationEthical approval for the study was granted on 18 February 2013.ResultsThe results of this study will be reported through peer-reviewed journals, conference presentations and an internal organisational report.Trial registration numbersNCT01827735, ISRCTN27852285, DRN767.

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Dataset Information

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

Background

Methods and findings

Conclusions

Trial registration

Publications

Regulatory T Cell Responses in Participants with Type 1 Diabetes after a Single Dose of Interleukin-2: A Non-Randomised, Open Label, Adaptive Dose-Finding Trial.

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