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Targeting regulatory T cells with Interleukin-2 treatment in type 1 diabetes: a response-adaptive, non-randomised, open-label trial of repeat doses of Aldesleukin (DILfrequency)

Eleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L Pekaiski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, View ORCID ProfileFrank Waldron-Lynch
doi: https://doi.org/10.1101/223958
Eleonora Seelig
1, (E Seelig MD, L Porter PhD, J Heywood PhD, J Kennet BSc, K Anselmiova BS, F Waldron-Lynch FRCPI)
2, (E Seelig MD, J Kennet BSc, K Anselmiova BS, M Evans FRCP, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
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James Howlett
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
5, (J Howlett MSc, A Mander PhD, S Bond PhD)
6, (J Howlett MSc, E Arbon PhD, S Bond PhD, F Waldron-Lynch FRCPI)
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Linsey Porter
1, (E Seelig MD, L Porter PhD, J Heywood PhD, J Kennet BSc, K Anselmiova BS, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
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Lucy Truman
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
7, (L Truman FRCS)
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James Heywood
1, (E Seelig MD, L Porter PhD, J Heywood PhD, J Kennet BSc, K Anselmiova BS, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
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Jane Kennet
1, (E Seelig MD, L Porter PhD, J Heywood PhD, J Kennet BSc, K Anselmiova BS, F Waldron-Lynch FRCPI)
2, (E Seelig MD, J Kennet BSc, K Anselmiova BS, M Evans FRCP, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
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Emma L Arbon
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
6, (J Howlett MSc, E Arbon PhD, S Bond PhD, F Waldron-Lynch FRCPI)
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Katerina Anselmiova
1, (E Seelig MD, L Porter PhD, J Heywood PhD, J Kennet BSc, K Anselmiova BS, F Waldron-Lynch FRCPI)
2, (E Seelig MD, J Kennet BSc, K Anselmiova BS, M Evans FRCP, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
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Neil M. Walker
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
8, (N Walker MA)
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Ravinder Atkar
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
9, (R Atkar MRCP)
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Marcin L Pekaiski
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
10, (M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD)
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Ed Rytina
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
11, (E Rytina FRCPath)
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Mark Evans
2, (E Seelig MD, J Kennet BSc, K Anselmiova BS, M Evans FRCP, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
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Linda S. Wicker
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
10, (M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD)
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John A. Todd
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
10, (M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD)
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Adrian P. Mander
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
5, (J Howlett MSc, A Mander PhD, S Bond PhD)
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Simon Bond
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
5, (J Howlett MSc, A Mander PhD, S Bond PhD)
6, (J Howlett MSc, E Arbon PhD, S Bond PhD, F Waldron-Lynch FRCPI)
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Frank Waldron-Lynch
1, (E Seelig MD, L Porter PhD, J Heywood PhD, J Kennet BSc, K Anselmiova BS, F Waldron-Lynch FRCPI)
2, (E Seelig MD, J Kennet BSc, K Anselmiova BS, M Evans FRCP, F Waldron-Lynch FRCPI)
3, (E Seelig MD, J Howlett MSc, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, E Arbon PhD, K Anselmiova BS, N Walker MA, R Atkar MRCP, M Pekalski PhD, E Rytina FRCPath, M Evans FRCP, Prof L Wicker PhD, Prof J Todd PhD, A Mander PhD, S Bond PhD, F Waldron-Lynch FRCPI)
4, (E Seelig MD, L Porter PhD, L Truman FRCS, J Heywood PhD, J Kennet BSc, K Anselmiova BS, N Walker MA, M Pekalski PhD, Prof L Wicker PhD, Prof J Todd PhD, F Waldron-Lynch FRCPI
6, (J Howlett MSc, E Arbon PhD, S Bond PhD, F Waldron-Lynch FRCPI)
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  • ORCID record for Frank Waldron-Lynch
  • For correspondence: fw211@cam.ac.uk
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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

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted November 28, 2017.
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Targeting regulatory T cells with Interleukin-2 treatment in type 1 diabetes: a response-adaptive, non-randomised, open-label trial of repeat doses of Aldesleukin (DILfrequency)
Eleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L Pekaiski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, Frank Waldron-Lynch
bioRxiv 223958; doi: https://doi.org/10.1101/223958
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Targeting regulatory T cells with Interleukin-2 treatment in type 1 diabetes: a response-adaptive, non-randomised, open-label trial of repeat doses of Aldesleukin (DILfrequency)
Eleonora Seelig, James Howlett, Linsey Porter, Lucy Truman, James Heywood, Jane Kennet, Emma L Arbon, Katerina Anselmiova, Neil M. Walker, Ravinder Atkar, Marcin L Pekaiski, Ed Rytina, Mark Evans, Linda S. Wicker, John A. Todd, Adrian P. Mander, Simon Bond, Frank Waldron-Lynch
bioRxiv 223958; doi: https://doi.org/10.1101/223958

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