T1DM Immunotherapy Using Polyclonal Tregs + IL-2 (TILT)
|ClinicalTrials.gov Identifier: NCT02772679|
Recruitment Status : Active, not recruiting
First Posted : May 13, 2016
Last Update Posted : December 16, 2020
|Condition or disease||Intervention/treatment||Phase|
|Type 1 Diabetes Mellitus||Biological: PolyTregs+IL-2||Phase 1|
The investigators hypothesize that ex vivo expanded human autologous CD4+CD127lo/-CD25+ polyclonal regulatory T cells (Polyclonal Tregs) plus Interleukin-2 (IL-2) administered to patients with Type 1 Diabetes Mellitus (T1DM) will be safe and biologically active. A Phase I trial with this cellular therapy plus IL-2 will lead the way for Phase II trials that test for efficacy based on preservation of C-peptide, reduced exogenous insulin requirements and improved glycemic control.
This is a Phase I safety/dosing study of Polyclonal Tregs + IL-2 in patients with T1DM.
The Tregs will be expanded using an established protocol utilizing anti-CD3/anti-CD28 beads plus IL-2. The study will involve 2 dosing cohorts of 6-8 T1DM patients each. The primary objective of this study is to assess the safety of Tregs + IL-2 and survival of Tregs in patients with recent onset T1DM who receive infusions of autologous Tregs + IL-2. The study will also assess potential effects of Tregs on beta cell function and the autoimmune response.
Subjects will receive Polyclonal Tregs at doses of 3 or 20x10^6 cells/kg. The dose of Tregs is selected based on a combination of considerations of manufacturing capacity, a predicted efficacious dose, and the available safety data of the Treg product currently in clinical trials. The IL-2 dose will be 1 x10^6 IU subcutaneously, given daily for 5 consecutive days at the completion of the cell infusion and again after 1 month. This dose is based on recent studies from Klatzmann et al. in T1DM, where the dose was found to be effective in a selective Treg expansion, well tolerated, and without an acute decline in beta cell function (Rosenzwajg et al., 2015).
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||16 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase 1 Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy With Interleukin-2 for the Treatment of Type 1 Diabetes|
|Study Start Date :||August 2016|
|Estimated Primary Completion Date :||July 2021|
|Estimated Study Completion Date :||December 2021|
Patients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2
PolyTregs will be infused into the patient in a single infusion. The first cohort will receive 3 x10^6 cells. The second cohort will receive 20x10^6 cells. Following the day 0 infusion of polyclonal Tregs, subjects will receive two 5-day courses of IL-2 (1 x 106 IU daily), the first on days 3-7 and the second on days 38-42. Administration of the second course of IL-2 may be delayed or withheld depending on threshold criteria for peripheral blood Treg frequencies and MMTT-stimulated C-peptide levels determined on day 28.
- Adverse events [ Time Frame: up to 3 years ]Adverse events of special interest: including infections, malignancies, safety of Treg infusions, and local and systemic reactions to IL-2.
- Survival of Tregs [ Time Frame: up to 3 years ]Comparison of the survival of graded doses of Tregs and IL-2. Calculating the half-life of infused deuterium-labeled Tregs in peripheral circulation will be used to assess the survival of Tregs.
- C-peptide response [ Time Frame: up to 3 years ]Change in beta cell function over time, as assessed by change in C-peptide area under curve in response to serial mixed meal tolerance tests. Analysis will include a comparison to recent data available from TrialNet placebo treated subjects.
- Insulin use [ Time Frame: up to 3 years ]Insulin use in units per kilogram body weight per day
- HbA1c levels [ Time Frame: up to 3 years ]
- Severe hypoglycemic events [ Time Frame: up to 3 years ]Severe hypoglycemic events as defined by the inability to selftreat and/or the requirement for glucagon injection
- Proportion of subjects who achieve at least a 13-week reduction in insulin dose to < 0.5 units/kg in each treatment arm [ Time Frame: up to 3 years ]
- Analysis of the effects of IL-2 on Treg kinetics and phenotype [ Time Frame: up to 3 years ]
- Levels of unmethylated insulin DNA (assay of beta cell death) [ Time Frame: up to 3 years ]
- Analysis of autoantibodies, enumeration and phenotypes islet antigen tetramer+ CD8, intracellular cytokine staining of T cells, serum proteomics, cytokines, and Treg phenotyping and functional assays [ Time Frame: up to 3 years ]
- Analysis of general immune response as assessed by, for example, viral tetramer+ CD8 cells and effects of Treg infusions on peripheral blood cells measured by flow cytometry including T cell subsets, B cells and other innate cell subsets [ Time Frame: up to 3 years ]
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02772679
|United States, California|
|University of California, San Francisco Medical Center|
|San Francisco, California, United States, 94143|
|United States, Connecticut|
|New Haven, Connecticut, United States, 06519|