Clinical Application of Stem Cell Educator Therapy in Type 1 Diabetes

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease that causes a deficit of pancreatic islet beta cells. Millions of individuals worldwide have T1D, and incidence increases annually. Several recent clinical trials point to the need for an approach that produces comprehensive immune modulation at both the local pancreatic and systemic levels. Stem Cell Educator (SCE) therapy offers comprehensive immune modulation at both the local and systemic levels in T1D by using a patient's own immune cells (including platelets) that are "educated" by cord blood stem cells. Tested clinically in more than 200 patients, SCE therapy has shown lasting reversal in autoimmunity in T1D patients, including improved C-peptide levels, reduced median glycated hemoglobin A1C (HbA1C) values, and decreased median daily usage of insulin. SCE therapy circulates a patient's blood through a blood cell separator, briefly cocultures the patient's immune cells with adherent Cord Blood Stem Cells (CB-SCs) in vitro, and returns the "educated" autologous immune cells to the patient's circulation.

Study Overview

• Status: Recruiting
• Conditions: Type 1 Diabetes
• Intervention / Treatment: Combination product: Stem Cell Educator therapy

Detailed Description

The SCE device is made of a hydrophobic material from FDA-approved (USP Class VI) dishes that tightly binds stem cells CB-SCs without interfering with their immune modulating capability. We originally designed a chamber for co-culture of lymphocytes and CB-SCs that included nine discs of the material with a flow pathway and adherent CB-SCs sandwiched between a top cover plate and a bottom collecting plate. In this trial, we are going to use the 12-layer SCE device.

The SCE therapy carried a lower risk of infection than a typical blood transfusion, and did not introduce stem cells or reagents into the patients. In addition, CB-SCs have very low immunogenicity, and the CB-SCs cultured in the device are a highly restricted population and contain no CD3+ T cells or other lymphocyte subsets, eliminating the need for human leukocyte antigen (HLA) matching prior to treatment. This innovative approach has the potential to provide CB-SC-mediated immune modulation therapy for multiple autoimmune diseases while mitigating the safety and ethical concerns associated with other approaches such as T1D, type 2 diabetes (T2D), and alopecia areata (AA) in clinics. The relative simplicity of the approach may also provide cost and time savings relative to other approaches.

• Study Type: Interventional
• Enrollment (Anticipated): 50
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: YONG ZHAO, MD,PhD; Phone Number: 201 988 0290; Email: Yong.Zhao@ThroneBio.com

Study Locations

• United States
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Active, not recruiting
      • Hackensack Meridian Health
    • Paramus, New Jersey, United States, 07652
      • Recruiting
      • Throne Biotechnologies
      • Contact: Yong Zhao, MD,PhD; Phone Number: 201-988-0290; Email: yong.zhao@thronebio.com
      • Principal Investigator: Boris Veysman, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Adult patients ( 14 years)
2. Must have a diagnosis of type 1 diabetes mellitus based on the 2015 American Diabetes Association criteria for the Clarification and Diagnosis of diabetes.
3. Must have a blood test confirming the presence of at least one autoantibody to pancreatic islet Cells (IAA, IA2, GAD 65, ZnT8).
4. Fasting C-peptide level > 0.3 ng/ml
5. HbA1C < 10% at enrollment
6. Recent diagnosis (within two years of enrollment)
7. Adequate venous access for apheresis
8. Must be equipped with a continuous glucose monitoring system (CGMS)
9. Ability to provide informed consent
10. For female patients only, willingness to use FDA-recommended birth control (http://www.fda.gov/downloads/ForConsumers/ByAudience/ForWomen/FreePublications/UCM356451.pdf) until 6 months post treatment.
11. Must agree to comply with all study requirements and be willing to complete all study visits

Exclusion Criteria:

1. AST or ALT 2 > x upper limit of normal.
2. Abnormal bilirubin (total bilirubin > 1.2 mg/dL, direct bilirubin > 0.4 mg/dL)
3. Creatinine > 2.0 mg/dl.
4. Known coronary artery disease or EKG suggestive of coronary artery disease unless cardiac clearance for apheresis is obtained from a cardiologist.
5. Known active infection such as Hepatitis B, Hepatitis C, or Human Immunodeficiency Virus (HIV)
6. Pregnancy assessed by a positive serum pregnancy test or breastfeeding mothers
7. Use of immunosuppressive medication within one month of enrollment including but not limited to prednisone, cyclosporine, tacrolimus, sirolimus, and chemotherapy.
8. Presence of any other autoimmune diseases (lupus, rheumatoid arthritis, scleroderma, etc.)
9. Anticoagulation other than ASA.
10. Hemoglobin < 10 g/dl or platelets < 100 k/ml
11. Is unable or unwilling to provide informed consent
12. Presence of any other physical or psychological medical condition that, in the opinion of the investigator, would preclude participation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment of T1D with Stem Cell Educator therapy; Recruited T1D subjects will receive one treatment with SCE therapy.	Combination product: Stem Cell Educator therapy; Patients with T1D will be evaluated by the study principal investigator or co-investigators. Informed consent will be obtained at the initial screening visit. The initial screening visit will occur within 30 days of initiation of SCE therapy. The second screening visit will occur within 7 days of therapy. Subjects who meet all criteria will be scheduled for treatment. All enrolled subjects will receive treatment with the SCE system consisting of a single session of mononuclear cells (MNC) collection by apheresis where 10 L of blood will be processed on day -1. The MNC product will then be exposed over to the SCE and on day 0 the product will be infused intravenously back to the patient.
Experimental: Conventional insulin therapy; Control group will receive conventional insulin therapy.	Combination product: Stem Cell Educator therapy; Patients with T1D will be evaluated by the study principal investigator or co-investigators. Informed consent will be obtained at the initial screening visit. The initial screening visit will occur within 30 days of initiation of SCE therapy. The second screening visit will occur within 7 days of therapy. Subjects who meet all criteria will be scheduled for treatment. All enrolled subjects will receive treatment with the SCE system consisting of a single session of mononuclear cells (MNC) collection by apheresis where 10 L of blood will be processed on day -1. The MNC product will then be exposed over to the SCE and on day 0 the product will be infused intravenously back to the patient.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment Adverse Events in T1D Subjects	The occurrence of treatment-related adverse events will be evaluated post the treatment with SCE therapy.	6 month

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Preliminary efficacy of SCE therapy to improve beta cell function	Preliminary efficacy as measured by Area under the C-peptide curve (AUC) over the first 2 hours of a 3-hour mixed meal tolerance test (MMTT)	12 months
Preliminary efficacy of SCE therapy to improve glucose control	Change in HbA1C levels over time	12 months
Preliminary efficacy of SCE therapy to reduce insulin dose	Change in daily insulin requirements	12 months
Efficacy of SCE therapy in immune modulation	Measurements of immune markers at baseline, 1, 3, 6, 9, and 12 months. Peripheral blood mononuclear cells (PBMC) will be collected and tested by flow cytometry.	12 month

Collaborators and Investigators

• Sponsor: Throne Biotechnologies Inc.
• Collaborators: Hackensack Meridian Health
• Investigators: Study Chair: YONG ZHAO, MD,PhD, Throne Biotechnologies Inc.

Publications and helpful links

General Publications

• Zhao Y, Knight CM, Jiang Z, Delgado E, Van Hoven AM, Ghanny S, Zhou Z, Zhou H, Yu H, Hu W, Li H, Li X, Perez-Basterrechea M, Zhao L, Zhao Y, Giangola J, Weinberg R, Mazzone T. Stem Cell Educator therapy in type 1 diabetes: From the bench to clinical trials. Autoimmun Rev. 2022 May;21(5):103058. doi: 10.1016/j.autrev.2022.103058. Epub 2022 Jan 31.
• Zhao Y, Jiang Z, Zhao T, Ye M, Hu C, Yin Z, Li H, Zhang Y, Diao Y, Li Y, Chen Y, Sun X, Fisk MB, Skidgel R, Holterman M, Prabhakar B, Mazzone T. Reversal of type 1 diabetes via islet beta cell regeneration following immune modulation by cord blood-derived multipotent stem cells. BMC Med. 2012 Jan 10;10:3. doi: 10.1186/1741-7015-10-3.
• Zhao Y. Stem cell educator therapy and induction of immune balance. Curr Diab Rep. 2012 Oct;12(5):517-23. doi: 10.1007/s11892-012-0308-1.
• Delgado E, Perez-Basterrechea M, Suarez-Alvarez B, Zhou H, Revuelta EM, Garcia-Gala JM, Perez S, Alvarez-Viejo M, Menendez E, Lopez-Larrea C, Tang R, Zhu Z, Hu W, Moss T, Guindi E, Otero J, Zhao Y. Modulation of Autoimmune T-Cell Memory by Stem Cell Educator Therapy: Phase 1/2 Clinical Trial. EBioMedicine. 2015 Nov 5;2(12):2024-36. doi: 10.1016/j.ebiom.2015.11.003. eCollection 2015 Dec.
• Zhao Y, Jiang Z, Delgado E, Li H, Zhou H, Hu W, Perez-Basterrechea M, Janostakova A, Tan Q, Wang J, Mao M, Yin Z, Zhang Y, Li Y, Li Q, Zhou J, Li Y, Martinez Revuelta E, Maria Garcia-Gala J, Wang H, Perez-Lopez S, Alvarez-Viejo M, Menendez E, Moss T, Guindi E, Otero J. Platelet-Derived Mitochondria Display Embryonic Stem Cell Markers and Improve Pancreatic Islet beta-cell Function in Humans. Stem Cells Transl Med. 2017 Aug;6(8):1684-1697. doi: 10.1002/sctm.17-0078. Epub 2017 Jul 7.

Helpful Links

• Throne Biotechnologies Inc

Study record dates

Study Major Dates

• Study Start (Actual): September 20, 2022
• Primary Completion (Anticipated): March 20, 2023
• Study Completion (Anticipated): March 20, 2024

Study Registration Dates

• First Submitted: July 4, 2019
• First Submitted That Met QC Criteria: July 4, 2019
• First Posted (Actual): July 8, 2019

Study Record Updates

• Last Update Posted (Actual): September 22, 2022
• Last Update Submitted That Met QC Criteria: September 19, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• 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: 2019-TH-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes