T1DM Immunotherapy Using CD4+CD127lo/-CD25+ Polyclonal Tregs

NCT ID: NCT01210664

Last Updated: 2018-07-11

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 16 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-11-30
• Study Completion Date: 2017-01-31

Brief Summary

The investigational therapy under study in this trial, regulatory T cells (Tregs), offers the hope of stabilizing further destruction of insulin producing beta cells in type 1 diabetes. Tregs are a specialized subset of T cells that function to control the immune response. Pre-clinical studies in non-obese diabetic mice have demonstrated that adoptive transfer of Tregs can slow diabetes progression and, in some cases, reverse new onset diabetes. The primary purpose of this Phase 1 study is to assess the safety and feasibility of intravenous infusion of ex vivo selected and expanded autologous polyclonal Tregs in patients with type 1 diabetes (T1DM) to support dose selection for a future efficacy trial. The study also aims to assess the effect of Tregs on beta cell function as well as on other measures of diabetes severity and the autoimmune response underlying T1DM.

Detailed Description

Currently, there is no approved medical treatment for preservation of the body's ability to produce insulin in patients with Type 1 Diabetes Mellitus (T1DM), and the progression of the disease can have devastating consequences. Inadequate blood glucose control results in many long term complications including kidney disease, blindness, amputation and nerve damage. In spite of the advances in insulin therapy and subsequent glucose control, patients are required to infuse insulin subcutaneously daily throughout their lives, monitor their diet and blood sugar levels, and deal with life-long uncertainties. The investigational therapy under study in this trial, regulatory T cells (Tregs), offers the hope of stabilizing diabetes. Tregs are a specialized subset of T cells that function to control the immune response. Pre-clinical studies in non-obese diabetic mice have demonstrated that adoptive transfer of Tregs can slow diabetes progression and, in some cases, reverse new onset diabetes. The primary objective of this study is to assess the safety of a single intravenous infusion of Tregs in patients with T1DM. The study will also assess the effect of Tregs on insulin-producing beta cell function as well as other outcomes related to diabetes management. Researchers will isolate Tregs from the patient's own blood using specific T cell surface markers (CD4, CD25, and CD127). This subset of cells is then expanded in the laboratory by co-stimulating with anti-CD3 and anti-CD28 immobilized on magnetic beads, and with the use of growth medium containing human serum and IL-2. Following the 14-day expansion, anti-CD3/anti-CD28 beads will be removed and the Tregs will be concentrated and consolidated. The cells will then be resuspended in sterile infusion solution at the required concentration and infused back into the patient through a standard peripheral intravenous line. Subjects will be observed overnight in the clinical research center for any possible side effects following the infusion. A total of 14 subjects will be enrolled. The study will involve 4 dosing cohorts with 3 or 4 adults in each cohort. Each cohort will receive increasing amounts of Tregs. Subjects will be followed over five years to assess safety of the Treg therapy.

Conditions

Type 1 Diabetes Mellitus

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Polyclonal Regulatory T Cells

Patients with Type 1 Diabetes Mellitus will have their regulatory T cells (Tregs) isolated by researchers and receive Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells by infusion

Group Type: EXPERIMENTAL

Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells

Intervention Type: BIOLOGICAL

The researchers will multiply/expand the Tregs in the laboratory using anti-CD3/anti-CD28 coated beads plus IL-2. Then, the Tregs will be infused back into the patient in a single infusion. The first cohort will receive 0.05 x10\^8 cells. The second cohort will receive 0.4 x10\^8 cells. The third cohort will receive 3.2 x10\^8 cells. The fourth cohort will receive 26 x10\^8 cells.

Interventions

Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells

The researchers will multiply/expand the Tregs in the laboratory using anti-CD3/anti-CD28 coated beads plus IL-2. Then, the Tregs will be infused back into the patient in a single infusion. The first cohort will receive 0.05 x10\^8 cells. The second cohort will receive 0.4 x10\^8 cells. The third cohort will receive 3.2 x10\^8 cells. The fourth cohort will receive 26 x10\^8 cells.

Intervention Type: BIOLOGICAL

Other Intervention Names

Tregs

Eligibility Criteria

Inclusion Criteria

• Diagnosis of T1DM within >3 and <24 months of screening according to the American Diabetes Association criteria
• Between 18 and 45 years of age
• Positive test for Epstein-Barr antibody
• Positive test for at least one of the following antibodies:

• ICA512-antibody
• ICA
• GAD65-antibody
• Insulin (if assessed within 10 days of the onset of insulin therapy)
• ZnT8
• Peak C-peptide >0.1 pmol/ml (>0.3 ng/ml) during MMTT challenge
• Adequate venous access to support draw of 400 ml whole blood and infusion of investigational therapy

Exclusion Criteria

• Hemoglobin <10.0 g/dL; leukocytes <3,000/µL; neutrophils <1,500/µL; lymphocytes <800/µL; platelets <100,000/µL
• Regulatory T cells present in peripheral blood at <10 per µl as determined by flow cytometry
• Serologic evidence of HIV-1 or HIV-2 infection
• Evidence of current hepatitis B as demonstrated by HBsAg or circulating hepatitis B genomes
• Serologic evidence of hepatitis C infection
• Detectable circulating EBV or CMV genomes or active infection
• Positive PPD skin test defined as greater than or equal to 10 mm induration
• 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 7.5mg of prednisone (or the equivalent) within 6 months prior to study entry will be excluded.
• History of malignancy ( including squamous cell carcinoma of the skin or cervix) except adequately treated basal cell carcinoma
• Any chronic illness or prior treatment which in the opinion of the investigator should preclude participation in the trial
• Pregnant or breastfeeding women, any female who is unwilling to use a reliable and effective form of contraception for 2 years afer Treg dosing and any male who is unwilling to use a reliable and effective form of contraception for 3 months after Treg dosing.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 45 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Juvenile Diabetes Research Foundation

OTHER

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: collaborator

University of California, San Francisco

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen E Gitelman, MD

Role: STUDY_CHAIR

University of California, San Francisco

Jeffrey Bluestone, PhD

Role: STUDY_DIRECTOR

University of California, San Francisco

Kevan Herold, MD

Role: PRINCIPAL_INVESTIGATOR

Yale University

Locations

University of California, San Francisco Medical Center

San Francisco, California, United States

Yale University

New Haven, Connecticut, United States

Countries

United States

References

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Other Identifiers

JDRF4-2005-1168

Identifier Type: OTHER_GRANT

Identifier Source: secondary_id

UCSFDC411AI

Identifier Type: -

Identifier Source: org_study_id