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

NCT01210664 | Completed Phase 1 Results DMC

• 2 other identifiers: UCSFDC411AIJDRF4-2005-1168
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 2

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.

Conditions

Type 1 Diabetes Mellitus

Keywords

Diabetes; Treg

Outcome Measures

Primary Outcomes (2)

• 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 Outcomes (3)

• Percent Change From Baseline in C-peptide Area Under the Curve

  26 and 52 weeks from baseline

• Insulin Use

  up to 104 weeks

• Hemoglobin A1c

  Up to 104 weeks

Study Arms (1)

Polyclonal Regulatory T Cells

EXPERIMENTAL

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

Interventions

Ex vivo Expanded Human Autologous Polyclonal Regulatory T Cells 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.

Also known as: Tregs

Polyclonal Regulatory T Cells

Eligibility Criteria

• Age: 18 Years - 45 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of California, San Francisco: lead
• Juvenile Diabetes Research Foundation: collaborator
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (2)

University of California, San Francisco Medical Center

San Francisco, California, 94143, United States

Location

Yale University

New Haven, Connecticut, 06519, United States

Location

Related Publications (15)

• 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.

  PMID: 17641665 BACKGROUND

• 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.

  PMID: 17491669 BACKGROUND

• 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.

  PMID: 19366777 BACKGROUND

• 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.

  PMID: 16903917 BACKGROUND

• 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.

  PMID: 15184499 BACKGROUND

• 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.

  PMID: 16818678 BACKGROUND

• 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.

  PMID: 19074986 BACKGROUND

• 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.

  PMID: 18352851 BACKGROUND

• 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.

  PMID: 19509133 BACKGROUND

• 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.

  PMID: 11786906 BACKGROUND

• 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.

  PMID: 17127428 BACKGROUND

• 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.

  PMID: 17942684 BACKGROUND

• 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.

  PMID: 26606968 RESULT

• 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.

  PMID: 34324441 DERIVED

• 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.

  PMID: 27133597 DERIVED

MeSH Terms

Conditions

Diabetes Mellitus, Type 1; Diabetes Mellitus

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Autoimmune Diseases; Immune System Diseases

Results Point of Contact

• Title: Jeffrey Bluestone, PhD
• Organization: University of California San Francisco Diabetes Center

jeff.bluestone@ucsf.edu

415-502-5677

Study Officials

• Stephen E Gitelman, MD

  University of California, San Francisco

  STUDY CHAIR

• Jeffrey Bluestone, PhD

  University of California, San Francisco

  STUDY DIRECTOR

• Kevan Herold, MD

  Yale University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 23, 2010
• First Posted: September 28, 2010
• Study Start: November 1, 2010
• Primary Completion: December 1, 2016
• Study Completion: January 1, 2017
• Last Updated: July 11, 2018
• Results First Posted: July 11, 2018

Record last verified: 2018-06

Locations

US (2)