T1DM Immunotherapy Using CD4+CD127lo/-CD25+ Polyclonal Tregs (Treg)

A Phase I Safety Trial of CD4+CD127lo/-CD25+ Polyclonal Treg Adoptive Immunotherapy for the Treatment of Type 1 Diabetes

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.

Study Overview

• Status: Completed
• Conditions: Type 1 Diabetes Mellitus
• Intervention / Treatment: Biological: Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells

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.

• Study Type: Interventional
• Enrollment (Actual): 16
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94143
      • University of California, San Francisco Medical Center
  • Connecticut
    • New Haven, Connecticut, United States, 06519
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Biological: 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.; Other Names: Tregs

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events (AEs) as a Measure of Safety and Tolerability	The number of AEs are reported by cohort and severity.	Mean follow-up of 31 months
Number of Participants Experiencing Severe or Life Threatening Laboratory Abnormalities	Laboratory measures tested include: hematology, blood chemistry, endocrine values, autoantibodies, and ophthalmologic exam results Total number of participants experiencing severe or life-threatening laboratory abnormalities is reported for each cohort. Events reported include hyperglycemia and hypoglycemia.	Mean follow-up of 31 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in C-peptide Area Under the Curve	Secondary diabetes-related outcome measure: C-peptide response during mixed meal tolerance test at 26 and 52 weeks, reported as the change from baseline in the area under the curve.	26 and 52 weeks from baseline
Insulin Use	Secondary diabetes-related outcome measure will include insulin use	up to 104 weeks
Hemoglobin A1c	Secondary diabetes-related outcome measure will include hemoglobin A1c	Up to 104 weeks

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Juvenile Diabetes Research Foundation
• Investigators: Principal Investigator: Kevan Herold, MD, Yale University; Study Chair: Stephen E Gitelman, MD, University of California, San Francisco; Study Director: Jeffrey Bluestone, PhD, University of California, San Francisco

Publications and helpful links

General Publications

• Chatenoud L, Bluestone JA. CD3-specific antibodies: a portal to the treatment of autoimmunity. Nat Rev Immunol. 2007 Aug;7(8):622-32. doi: 10.1038/nri2134. Epub 2007 Jul 20.
• Couri CE, Oliveira MC, Stracieri AB, Moraes DA, Pieroni F, Barros GM, Madeira MI, Malmegrim KC, Foss-Freitas MC, Simoes BP, Martinez EZ, Foss MC, Burt RK, Voltarelli JC. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed type 1 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1573-9. doi: 10.1001/jama.2009.470.
• Putnam AL, Brusko TM, Lee MR, Liu W, Szot GL, Ghosh T, Atkinson MA, Bluestone JA. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes. 2009 Mar;58(3):652-62. doi: 10.2337/db08-1168. Epub 2008 Dec 15.
• Tang Q, Bluestone JA. Regulatory T-cell physiology and application to treat autoimmunity. Immunol Rev. 2006 Aug;212:217-37. doi: 10.1111/j.0105-2896.2006.00421.x.
• Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med. 2004 Jun 7;199(11):1455-65. doi: 10.1084/jem.20040139.
• Rapoport AP, Stadtmauer EA, Aqui N, Vogl D, Chew A, Fang HB, Janofsky S, Yager K, Veloso E, Zheng Z, Milliron T, Westphal S, Cotte J, Huynh H, Cannon A, Yanovich S, Akpek G, Tan M, Virts K, Ruehle K, Harris C, Philip S, Vonderheide RH, Levine BL, June CH. Rapid immune recovery and graft-versus-host disease-like engraftment syndrome following adoptive transfer of Costimulated autologous T cells. Clin Cancer Res. 2009 Jul 1;15(13):4499-507. doi: 10.1158/1078-0432.CCR-09-0418. Epub 2009 Jun 9.
• Levine BL, Bernstein WB, Aronson NE, Schlienger K, Cotte J, Perfetto S, Humphries MJ, Ratto-Kim S, Birx DL, Steffens C, Landay A, Carroll RG, June CH. Adoptive transfer of costimulated CD4+ T cells induces expansion of peripheral T cells and decreased CCR5 expression in HIV infection. Nat Med. 2002 Jan;8(1):47-53. doi: 10.1038/nm0102-47.
• Saudek F, Havrdova T, Boucek P, Karasova L, Novota P, Skibova J. Polyclonal anti-T-cell therapy for type 1 diabetes mellitus of recent onset. Rev Diabet Stud. 2004 Summer;1(2):80-8. doi: 10.1900/RDS.2004.1.80. Epub 2004 Aug 10.
• Liu W, Putnam AL, Xu-Yu Z, Szot GL, Lee MR, Zhu S, Gottlieb PA, Kapranov P, Gingeras TR, Fazekas de St Groth B, Clayberger C, Soper DM, Ziegler SF, Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med. 2006 Jul 10;203(7):1701-11. doi: 10.1084/jem.20060772. Epub 2006 Jul 3.
• Levine BL. T lymphocyte engineering ex vivo for cancer and infectious disease. Expert Opin Biol Ther. 2008 Apr;8(4):475-89. doi: 10.1517/14712598.8.4.475.
• Miao D, Yu L, Eisenbarth GS. Role of autoantibodies in type 1 diabetes. Front Biosci. 2007 Jan 1;12:1889-98. doi: 10.2741/2195.
• Wenzlau JM, Juhl K, Yu L, Moua O, Sarkar SA, Gottlieb P, Rewers M, Eisenbarth GS, Jensen J, Davidson HW, Hutton JC. The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17040-5. doi: 10.1073/pnas.0705894104. Epub 2007 Oct 17.
• Bluestone JA, Buckner JH, Fitch M, Gitelman SE, Gupta S, Hellerstein MK, Herold KC, Lares A, Lee MR, Li K, Liu W, Long SA, Masiello LM, Nguyen V, Putnam AL, Rieck M, Sayre PH, Tang Q. Type 1 diabetes immunotherapy using polyclonal regulatory T cells. Sci Transl Med. 2015 Nov 25;7(315):315ra189. doi: 10.1126/scitranslmed.aad4134.
• Dong S, Hiam-Galvez KJ, Mowery CT, Herold KC, Gitelman SE, Esensten JH, Liu W, Lares AP, Leinbach AS, Lee M, Nguyen V, Tamaki SJ, Tamaki W, Tamaki CM, Mehdizadeh M, Putnam AL, Spitzer MH, Ye CJ, Tang Q, Bluestone JA. The effect of low-dose IL-2 and Treg adoptive cell therapy in patients with type 1 diabetes. JCI Insight. 2021 Sep 22;6(18):e147474. doi: 10.1172/jci.insight.147474.
• Gitelman SE, Bluestone JA. Regulatory T cell therapy for type 1 diabetes: May the force be with you. J Autoimmun. 2016 Jul;71:78-87. doi: 10.1016/j.jaut.2016.03.011. Epub 2016 Apr 28.

Study record dates

Study Major Dates

• Study Start: November 1, 2010
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: September 23, 2010
• First Submitted That Met QC Criteria: September 27, 2010
• First Posted (Estimate): September 28, 2010

Study Record Updates

• Last Update Posted (Actual): July 11, 2018
• Last Update Submitted That Met QC Criteria: June 12, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Diabetes; Treg
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Immune System Diseases; Autoimmune Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 1
• Other Study ID Numbers: UCSFDC411AI; JDRF4-2005-1168 (Other Grant/Funding Number: JDRF)