Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study

Truman, Lucy; Pękalski, Marcin Ł.; Kareclas, Paula; Evangelou, Marina; Walker, Neil M.; Howlett, James; Mander, Adrian; Kennet, Jane; Wicker, Linda S.; Bond, Simon; Todd, John A.; Waldron‐Lynch, Frank

doi:10.1136/bmjopen-2015-009799

Cited by 22 publications

(17 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in the same trial, other cell types also responded to IL-2 including Teff at all doses tested and there was significant heterogeneity across subjects. This finding confirms initial trials with IL-2 therapy in T1D that suggest there is a narrow dosing window that varies across subjects to achieve Treg- specifc tolerogenic effects [8, 9]. To this point, it is imperative to better understand patient heterogeneity and underlying mechanisms of disease by clearly defining the degree, cell source, and cause of variability in IL-2/IL-2R signaling.…”

Section: Introductionsupporting

confidence: 68%

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Schwedhelm¹,

Thorpe²,

Murray³

et al. 2017

Clinical Immunology

View full text Add to dashboard Cite

The IL-2/IL-2R pathway is implicated in type 1 diabetes (T1D). While its role in regulatory T cell (Treg) biology is well characterized, mechanisms that influence IL-2 responses in effector T cells (Teff) are less well understood. We compared IL-2 responses in 95 healthy control and 98 T1D subjects. In T1D, low IL-2 responsiveness was most pronounced in memory Teff. Unlike Treg, CD25 expression did not influence the Teff responses. Reduced IL-2 responses in memory Teff were not rescued by resting, remained lower after activation and proliferation, and were absent in type 2 diabetes. Comparing basal IL-2 responses in resting versus activated cells, memory Teff displayed lower, but more sustained, responses to IL-2 overtime. These results suggest that T1D–associated defects in the Teff compartment are due to intrinsic factors related to activation. Evaluation of both Teff and Treg IL-2R signaling defects in T1D subjects may inform selection of therapies.

show abstract

Section: Introductionsupporting

confidence: 68%

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Schwedhelm¹,

Thorpe²,

Murray³

et al. 2017

Clinical Immunology

View full text Add to dashboard Cite

show abstract

“…Tregs, Teffs, and CD25 expression on Tregs were defined within the CD3 + CD4 + FACS gate (Supplemental Appendix, Coprimary endpoints -definitions). The detailed gating strategy has been previously published (31). Secondary predefined clinical endpoints were change in Treg count and subsets, T effector count and subsets, NK cell frequency and count, full blood count and differential, IL-2 and hsCRP levels, autoantibodies, metabolic measures, and safety.…”

Section: Methodsmentioning

confidence: 99%

“…gov (NCT02265809). The study protocol was published in advance of the completion and final analysis of the trial (31). All participants provided written informed consent prior to their participation in the study.…”

Section: Methodsmentioning

confidence: 99%

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes

Seelig¹,

Howlett²,

Porter³

et al. 2018

JCI Insight

Self Cite

View full text Add to dashboard Cite

BACKGROUND. Type 1 diabetes (T1D) results from loss of immune regulation, leading to the development of autoimmunity to pancreatic β cells, involving autoreactive T effector cells (Teffs). Tregs, which prevent autoimmunity, require IL-2 for maintenance of immunosuppressive functions. Using a response-adaptive design, we aimed to determine the optimal regimen of aldesleukin (recombinant human IL-2) to physiologically enhance Tregs while limiting expansion of Teffs. METHODS. DILfrequency is a nonrandomized, open-label, response-adaptive study of participants, aged 18-70 years, with T1D. The initial learning phase allocated 12 participants to 6 different predefined regimens. Then, 3 cohorts of 8 participants were sequentially allocated dose frequencies, based on repeated interim analyses of all accumulated trial data. The coprimary endpoints were percentage change in Tregs and Teffs and CD25 (α subunit of the IL-2 receptor) expression by Tregs, from baseline to steady state. RESULTS. Thirty-eight participants were enrolled, with thirty-six 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 × 10 6 IU/m 2 (95% CI-0.007 to 0.485) every 3 days. Tregs and CD25 were dose-frequency responsive, Teffs were not. The commonest adverse event was injection site reaction (464 of 694 events). CONCLUSIONS. Using a response-adaptive design, aldesleukin treatment can be optimized. Our methodology can generally be employed to immediately access proof of mechanism, thereby leading to more efficient and safe drug development.

show abstract

“…This study clearly highlights the importance of carefully assessing the dose and frequency of IL-2 administration to selectively target Tregs while avoiding unwanted off-target effects. These issues are being investigated intensively in mechanistic studies with immunological endpoints prior to conducting fully powered Phase II efficacy trials [ 68 , 69 ].…”

Section: Promoting Immune Regulation In Type 1 Diabetesmentioning

confidence: 99%

Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it?

2017

View full text Add to dashboard Cite

Type 1 diabetes is an autoimmune disease characterised by the destruction of insulin producing beta cells in the pancreas. Whilst it remains unclear what the original triggering factors for this destruction are, observations from the natural history of human type 1 diabetes, including incidence rates in twins, suggest that the disease results from a combination of genetic and environmental factors. Whilst many different immune cells have been implicated, including members of the innate and adaptive immune systems, a view has emerged over the past 10 years that beta cell damage is mediated by the combined actions of CD4 + and CD8 + T cells with specificity for islet autoantigens. In health, these potentially pathogenic T cells are held in check by multiple regulatory mechanisms, known collectively as 'immunological tolerance'. This raises the question as to whether type 1 diabetes develops, at least in part, as a result of a defect in one or more of these control mechanisms. Immunological tolerance includes both central mechanisms (purging of the T cell repertoire of high-affinity autoreactive T cells in the thymus) and peripheral mechanisms, a major component of which is the action of a specialised subpopulation of T cells, known as regulatory T cells (Tregs). In this review, we highlight the evidence suggesting that a reduction in the functional capacity of different Treg populations contributes to disease development in type 1 diabetes. We also address current controversies regarding the putative causes of this defect and discuss strategies to correct it as a means to reduce or prevent islet destruction in a clinical setting.

show abstract

Protocol of the adaptive study of IL-2 dose frequency on regulatory T cells in type 1 diabetes (DILfrequency): a mechanistic, non-randomised, repeat dose, open-label, response-adaptive study

Cited by 22 publications

References 38 publications

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

Attenuated IL-2R signaling in CD4 memory T cells of T1D subjects is intrinsic and dependent on activation state

The DILfrequency study is an adaptive trial to identify optimal IL-2 dosing in patients with type 1 diabetes

Regulatory T cell dysfunction in type 1 diabetes: what’s broken and how can we fix it?

Contact Info

Product

Resources

About