Clinical trial NCT02772679: T1DM Immunotherapy Using Polyclonal Tregs + IL-2
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Type 1 Diabetes Mellitus
Keywords: Diabetes
Treg
Proluekin
Lead sponsor: University of California, San Francisco
Sponsor class: OTHER
Collaborators: name: Yale University
First posted: 2016-05-13
Enrollment: 16
Sex: ALL
Minimum age (years): 18
Maximum age (years): 45
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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 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).

Eligibility criteria: Inclusion Criteria:

1. Diagnosis of T1DM within \>3 and \<24 months of day 0 according to the American Diabetes Association standard criteria.
2. 18 to 45 years of age on day of screening visit.
3. 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).
4. Peak stimulated C-peptide level \>0.2 pmol/mL (0.6 ng/ml) following an MMTT.
5. Weight of \>= 40 kg and \<=90.7kg
6. 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:

1. Hemoglobin \<10.0 g/dL; leukocytes \<3,000/μL; neutrophils \<1,500/μL; lymphocytes \<800μL; platelets \<100,000/μL
2. 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).
3. 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.
4. 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.
5. History of malignancy (including squamous cell carcinoma of the skin or cervix) except adequately treated basal cell carcinoma
6. 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
7. Any condition that, in the investigator's opinion, may compromise study participation or may confound the interpretation of the study results.
8. 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.

Primary outcomes:
measure: Adverse events
timeFrame: up to 3 years
measure: Survival of Tregs
timeFrame: up to 3 years
Secondary outcomes:
measure: C-peptide response
timeFrame: up to 3 years
measure: Insulin use
timeFrame: up to 3 years
measure: HbA1c levels
timeFrame: up to 3 years
measure: Severe hypoglycemic events
timeFrame: up to 3 years
measure: Proportion of subjects who achieve at least a 13-week reduction in insulin dose to < 0.5 units/kg in each treatment arm
timeFrame: up to 3 years
measure: Analysis of the effects of IL-2 on Treg kinetics and phenotype
timeFrame: up to 3 years
measure: Levels of unmethylated insulin DNA (assay of beta cell death)
timeFrame: up to 3 years
measure: 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
timeFrame: up to 3 years
measure: 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
timeFrame: up to 3 years
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California, San Francisco Medical Center
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
Study officials:
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