T1DM Immunotherapy Using Polyclonal Tregs + IL-2 (TILT)
|Study Design:||Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||A Phase 1 Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy With Interleukin-2 for the Treatment of Type 1 Diabetes|
- Adverse events [ Time Frame: up to 3 years ] [ Designated as safety issue: Yes ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]Insulin use in units per kilogram body weight per day
- HbA1c levels [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
- Severe hypoglycemic events [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]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 ] [ Designated as safety issue: No ]
- Analysis of the effects of IL-2 on Treg kinetics and phenotype [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
- Levels of unmethylated insulin DNA (assay of beta cell death) [ Time Frame: up to 3 years ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
|Study Start Date:||July 2016|
|Estimated Study Completion Date:||December 2021|
|Estimated Primary Completion Date:||July 2021 (Final data collection date for primary outcome measure)|
Patients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2
Tregs 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.
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 3 dosing cohorts of 4 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 50x106, 350x106 or 1x109 cells. 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 1x106 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 selective Treg expansion, well tolerated, and without acute decline in beta cell function (Rosenzwajg et al., 2015).
Please refer to this study by its ClinicalTrials.gov identifier: NCT02772679
|Contact: Christine Torok, RN||415-502-9089||Christine.Torok@ucsf.edu|
|Contact: Tracy Rodriguez||415-476-5026||Tracy.Rodriguez@ucsf.edu|
|United States, California|
|University of California, San Francisco Medical Center||Not yet recruiting|
|San Francisco, California, United States, 94143|
|Contact: Christine Torok, RN 415-502-9089 Christine.Torok@ucsf.edu|
|Principal Investigator: Stephen E Gitelman, MD|
|United States, Connecticut|
|New Haven, Connecticut, United States, 06519|
|Principal Investigator:||Stephen Gitelman, M.D.||University of California, San Francisco|
|Principal Investigator:||Kevan Herold, M.D.||Yale University|