TILT: T1DM Immunotherapy Using Polyclonal Tregs + IL-2
Study Details
Study Description
Brief Summary
The purpose 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.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 1 |
Detailed Description
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 20x106 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 x106 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 Design
Arms and Interventions
Arm | Intervention/Treatment |
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Experimental: PolyTregs+IL-2 Patients with type 1 diabetes mellitus will receive ex vivo expanded human autologous polyclonal regulatory T cells plus IL-2 |
Biological: PolyTregs+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.
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Outcome Measures
Primary Outcome Measures
- Adverse events [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 [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.
Secondary Outcome Measures
- C-peptide response [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 [up to 3 years]
Insulin use in units per kilogram body weight per day
- HbA1c levels [up to 3 years]
- Severe hypoglycemic events [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 [up to 3 years]
- Analysis of the effects of IL-2 on Treg kinetics and phenotype [up to 3 years]
- Levels of unmethylated insulin DNA (assay of beta cell death) [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 [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 [up to 3 years]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Diagnosis of T1DM within >3 and <24 months of day 0 according to the American Diabetes Association standard criteria.
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18 to 45 years of age on day of screening visit.
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Positive for at least one islet cell autoantibody (glutamate decarboxylase; insulin, if obtained within 10 days of the onset of insulin therapy; ICA 512-antibody; and/or ZnT8).
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Peak stimulated C-peptide level >0.2 pmol/mL (0.6 ng/ml) following an MMTT.
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Weight of >= 40 kg and <=90.7kg
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Adequate venous access to support a blood draw of 5 mls/kg up to maximum of 400 ml whole blood and later infusion of investigational therapy
Exclusion Criteria:
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Hemoglobin <10.0 g/dL; leukocytes <3,000/μL; neutrophils <1,500/μL; lymphocytes <800μL; platelets <100,000/μL
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Any sign of significant chronic active infection (e.g., hepatitis, tuberculosis, EBV, or CMV), or screening laboratory evidence consistent with a significant chronic active infection (such as positive for HIV, PPD, or HBsAg).
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Anticipated ongoing use of diabetes medications other than insulin that affect glucose homeostasis, such as metformin, sulfonylureas, thiazolidinediones, glucagon-like peptide 1 (GLP-1) mimetics, dipeptidyl peptidase IV (DPP-IV) inhibitors, SGLT2 inhibitors, or amylin.
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Chronic use of systemic glucocorticoids or other immunosuppressive agents, or biologic immunomodulators within 6 months prior to study entry. Specifically, subjects who have received over 7 days of treatment with 7.5 mg of prednisone (or the equivalent) within 6 months prior to study entry will be excluded.
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History of malignancy (including squamous cell carcinoma of the skin or cervix) except adequately treated basal cell carcinoma
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Pregnant or breastfeeding women, or any female who is unwilling to use a reliable and effective form of contraception for 1 year after Treg +/- IL-2 dosing, and any male who is unwilling to use a reliable and effective form of contraception for 3 months after Treg +/- IL-2 dosing
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Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
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Patients who are unwilling to agree to not participate in another clinical trial, which in the opinion of the investigator may confound the results of this study, for at least 1 year following Treg infusion.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | University of California, San Francisco Medical Center | San Francisco | California | United States | 94143 |
2 | Yale University | New Haven | Connecticut | United States | 06519 |
Sponsors and Collaborators
- Jeffrey Bluestone
- Yale University
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
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- Salomon B, Bluestone JA. Complexities of CD28/B7: CTLA-4 costimulatory pathways in autoimmunity and transplantation. Annu Rev Immunol. 2001;19:225-52. Review.
- Sitrin J, Ring A, Garcia KC, Benoist C, Mathis D. Regulatory T cells control NK cells in an insulitic lesion by depriving them of IL-2. J Exp Med. 2013 Jun 3;210(6):1153-65. doi: 10.1084/jem.20122248. Epub 2013 May 6.
- Tang Q, Adams JY, Penaranda C, Melli K, Piaggio E, Sgouroudis E, Piccirillo CA, Salomon BL, Bluestone JA. Central role of defective interleukin-2 production in the triggering of islet autoimmune destruction. Immunity. 2008 May;28(5):687-97. doi: 10.1016/j.immuni.2008.03.016. Epub 2008 May 8.
- Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006 Aug;212:217-37. Review.
- Tang Q, Bluestone JA. The Foxp3+ regulatory T cell: a jack of all trades, master of regulation. Nat Immunol. 2008 Mar;9(3):239-44. doi: 10.1038/ni1572. Review.
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