Islet Transplantation With Recipient T-Reg Cells or Deceased Donor Vertebral Bone Marrow Therapy

Clinical Islet Transplantation With Apheresis, Isolation and Reintroduction of Recipient Regulatory T Cells or Administration of Deceased Donor Vertebral Bone Marrow in Type 1 Diabetes

The goal of this clinical trial is to learn if patients who have brittle type 1 diabetes receiving an islet transplantation will have better control of their sugars if they also receive one of 2 types of immune cells along with the islet transplant. The participants will receive either their own immune cells, called regulatory T cells, or immune cells from the bone marrow of the islet donor.

Study Overview

• Status: Not yet recruiting
• Conditions: Islet Transplantation
• Intervention / Treatment: Biological: Infusion of recipient T regulatory cell; Biological: Infusion of concomitant Donor Derived Vertebral Bone Marrow

Detailed Description

Islet transplantation success remains limited by the immediate loss of islet after transplantation, rejection, and side effect from immunosuppression. Preclinical animal models provide evidence that donor bone marrow cells OR regulatory T cells infused at the time of islet transplantation can improve the survival of islets after transplantation and reduce the need for immunosuppression. The purpose of this study is to evaluate the feasibility and safety of combining an islet transplant with the recipient's Tregs OR deceased donor bone marrow cells in patients with brittle type 1 diabetes.

• Study Type: Interventional
• Enrollment (Estimated): 24
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Stephan Busque, MD; Phone Number: 650-498-6189; Email: sbusque@stanford.edu
• Study Contact Backup: Name: Kevin Ly, BS; Phone Number: 650-497-6057; Email: kevinly@stanford.edu

Study Locations

• United States
  • California
    • Palo Alto, California, United States, 94305
      • Stanford University
      • Principal Investigator: Stephan Busque, MD
      • Principal Investigator: Everett Meyer, MD
      • Sub-Investigator: Marina Basina, MD
      • Contact: Kevin Ly, BS; Phone Number: 650-497-6057; Email: kevinly@stanford.edu
      • Contact: Stephan Busque, MD
      • Sub-Investigator: Avnesh S Thakor, MD, PhD
      • Sub-Investigator: Thomas A Pham, MD
      • Sub-Investigator: Kent P Jensen, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and female patients age 18 to 70 years of age.
• Ability to provide written informed consent.
• Mentally stable and able to comply with the procedures of the study protocol.
• Clinical history compatible with T1D with onset of disease at < 45 years of age, insulin- dependence for ≥ 5 years at the time of enrollment, or a sum of patient age and insulin dependent diabetes duration of ≥ 28.
• Absence of stimulated C peptide (< 0.3 ng/mL) in response to a mixed meal tolerance test measured at 60 and 90 minutes after the start of consumption
• Involvement in intensive diabetes management defined as self-monitoring of glucose values no less than a mean of three times each day averaged over each week and by the administration of three or more insulin injections each day or insulin pump therapy. Such management must be under the direction of an endocrinologist, diabetologist, or diabetes specialist with at least 3 clinical evaluations during the 12 months prior to study enrollment.
• At least two episodes of severe hypoglycemia in the 12 months prior to study enrollment.
• Reduced awareness of hypoglycemia as defined by a Clarke score of 4 or more OR a HYPO score greater than or equal to the 90th percentile (1047) during the screening period and within the last 6 months prior to randomization.
• Women of childbearing potential may be enrolled if a pregnancy test is negative, and they agree to the use of 2 forms of contraception from Screening to the end of the study. Males must agree to use 2 forms of contraception from Screening to the end of the study if their partners are of childbearing potential.

• Acceptable methods of birth control which must be used together are:

  • Oral contraceptive and condom (combination oral contraceptives containing the second- generation progestin (levonorgestrel) and <30 μg of estrogen should be utilized),
  • IUD and condom,
  • Diaphragm with spermicide and condom
• Subject must complete training on how to use the Tandem X2 pump with Control IQ technology by a certified Diabetes Educator or physician. Patients must complete at least 2 hour training to the satisfaction of the educator and show proficiency and understanding in its use as judged by the educator.
• Patients with prior kidney transplantation on immunosuppressive medications are eligible provided they meet all eligibility criteria above excluding the need for hypoglycemia unawareness. Patients should not be candidates for solid organ pancreas transplant or have declined the surgical option.
• Exclusion Criteria:
• Body mass index (BMI) >30 kg/m2 or patient weight ≤50kg.
• Insulin requirement of >1.0 IU/kg/day or <15 U/day. 3. HbA1c >10%.
• Treatment with any anti-diabetic medication other than insulin within 4 weeks of Screening
• Untreated proliferative diabetic retinopathy.
• Blood Pressure: SBP >180 mmHg or DBP >100 mmHg on optimal treatment.
• Estimated glomerular filtration rate of <50 mL/min/1.73m2.
• Presence or history of macroalbuminuria (>500mg/g creatinine).
• Presence or history of panel-reactive anti-HLA antibodies >50%. Negative cross- match by flow cytometry and no DSA to organ donor by standard methods.
• For female subjects: Positive pregnancy test, presently breast-feeding, or unwillingness to use effective contraceptive measures for the duration of the study and 4 months after discontinuation. For male participants: intent to procreate during the duration of the study or within 4 months after discontinuation or unwillingness to use effective measures of contraception
• Presence of active infection including hepatitis B, hepatitis C, HIV, or tuberculosis (TB). Subjects with laboratory evidence of active infection are excluded even in the absence of clinical evidence of active infection.
• Negative screen for Epstein-Barr Virus (EBV) by IgG determination.
• Invasive aspergillus, histoplasmosis, or coccidioidomycosis infection within one year prior to study enrollment.
• Any history of malignancy except for completely resected squamous or basal cell carcinoma of the skin.
• Known active alcohol or substance abuse.
• Baseline Hb below the lower limits of normal; neutropenia (<1,500/7L), or thrombocytopenia (platelets <100,000/7L).
• Any coagulopathy or medical condition requiring long-term anticoagulant therapy (e.g., warfarin) after islet transplantation (low-dose aspirin treatment is allowed) or patients with an international normalized ratio (INR) >1.5.

• Severe co-existing cardiac disease, characterized by any one of these conditions:

  • recent myocardial infarction (within past 6 months).
  • evidence of uncorrectable ischemia on functional cardiac exam within the last year.
  • left ventricular ejection fraction <30%.
• Persistent elevation of liver function tests at the time of study entry. Persistent serum glutamic-oxaloacetic transaminase (SGOT [AST]), serum glutamate pyruvate transaminase (SGPT [ALT]), or total bilirubin, with values > 1.5 times normal upper limits will exclude a patient.
• Acute or chronic pancreatitis.
• Treatment with any anti-diabetic medication other than insulin within 4 weeks of enrollment.
• Use of any investigational agents within 4 or more weeks of enrollment, depending upon the pharmacokinetics of the investigational agent and durability of changes with treatment in immune function or glycemic regulation.
• Administration of live attenuated vaccine(s) within 2 months of enrollment.
• Any medical condition that, in the opinion of the investigator, will interfere with safe participation in the trial.
• A previous islet transplant.
• History of medical non-adherence or poor social support.
• Individuals with selective IgA deficiencies (IgA level less than 15 mg/dL) who have known antibody against IgA.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Recipient T Regulatory Cell; T regulatory cells prior to islet transplantation, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).	Biological: Infusion of recipient T regulatory cell; Patients will undergo a single apheresis collection with a target total blood volume of 20-30 L and the collected cells used as the source of purified Tregs to be infused following the islet transplantation. In the event a patient is unable to meet the collection target, a second collection may be performed.
Experimental: Donor Derived Vertebral Bone Marrow; Deceased donor vertebral bone marrow (VBM) cells, induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF).	Biological: Infusion of concomitant Donor Derived Vertebral Bone Marrow; The cells from the donor VB and spleen are processed under cGMP conditions and released for infusion after the respective recipient has undergone transplant and conditioning. Under this protocol, the donor's VB will be obtained at the same time as the pancreatic islets and will be the source of HSC for infusion with the intent to establish immune tolerance to the donor's pancreatic islet cells. Subjects will receive one infusion of allogeneic cadaveric islets. Subjects will receive induction therapy with ATG and Belatacept and maintenance immunosuppression with Tacrolimus Extended-release tablets (Envarsus XR) and Mycophenolate Mofetil (MMF). After islet transplantation, the VBM cells will be infused in one time window: on day 0-1. Subjects will undergo closed-loop insulin pump glucose control peri-transplant.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration	Grade 3 to 5 cytokine release syndrome / acute infusion reaction after Treg administration infusion reaction after Treg administration	within 3 months
Occurrence of grade 4 or greater adverse events of islet transplantation	Adverse event grade 4 or greater	Within two years
Number of patients who receive Treg infusions (Arm1) or Donor Derived Vertebral Bone Marrow (Arm2) and islet transplantation (feasibility)	Number of patients who received planned Treg or Donor Bone Marrow	Within two years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
HbA1c ≤6.5%	HbA1c ≤6.5%	assessed at 6, 12 and 24 months post-islet transplantation
Absence of severe hypoglycemic events	Absence of severe hypoglycemic event , requiring intervention by other person than the patient	assessed at 6, 12 and 24 months post-islet transplantation
Decrease of insulin mean requirements (u/kg) from prior to transplantation by 50% of total daily dose	Reduction of exogenous insulin requirement by 50% from baseline	assessed at 6, 12 and 24 months post-islet transplantation
Clarke hypoglycemia severity (HYPO) score less than 2 (0 to >4, >4 indicate severe hypoglycemia unawareness)	Improvement of Clarke score to less than 2	assessed at 6, 12 and 24 months post-islet transplantation
Basal C-peptide at levels e >0.5 ng/mL (>0.17 nmol/L) fasting or stimulated.	C-petide production from islet transplant assessment	assessed at 6, 12 and 24 months post-islet transplantation
Target of glucose variability and hypoglycemia duration derived from the CGMS <Standard Deviation and Coefficient targets>	Monitoring of glucose control 24h sensor monitoring	assessed at 6, 12 and 24 months post-islet transplantation
Measurement of donor Specific Antibody, cPRA	Single bead luminex anti HLA class 1 and 2 assay	assessed at 6, 12 and 24 months post-islet transplantation
Quality of life (QOL) assessment	QOL questionnaire SF-12 (0-100, higher score is better outcome)	assessed at 6, 12 and 24 months post-islet transplantation

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: University of California, San Francisco
• Investigators: Principal Investigator: Stephan Busque, MD, Stanford University

Publications and helpful links

General Publications

• Ryan EA, Paty BW, Senior PA, Bigam D, Alfadhli E, Kneteman NM, Lakey JR, Shapiro AM. Five-year follow-up after clinical islet transplantation. Diabetes. 2005 Jul;54(7):2060-9. doi: 10.2337/diabetes.54.7.2060.
• Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med. 2000 Jul 27;343(4):230-8. doi: 10.1056/NEJM200007273430401.
• Hirsch IB. Insulin analogues. N Engl J Med. 2005 Jan 13;352(2):174-83. doi: 10.1056/NEJMra040832. No abstract available.
• Terasaki PI, Ozawa M. Predicting kidney graft failure by HLA antibodies: a prospective trial. Am J Transplant. 2004 Mar;4(3):438-43. doi: 10.1111/j.1600-6143.2004.00360.x.
• Mao Q, Terasaki PI, Cai J, Briley K, Catrou P, Haisch C, Rebellato L. Extremely high association between appearance of HLA antibodies and failure of kidney grafts in a five-year longitudinal study. Am J Transplant. 2007 Apr;7(4):864-71. doi: 10.1111/j.1600-6143.2006.01711.x.
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• Ryan EA, Shandro T, Green K, Paty BW, Senior PA, Bigam D, Shapiro AM, Vantyghem MC. Assessment of the severity of hypoglycemia and glycemic lability in type 1 diabetic subjects undergoing islet transplantation. Diabetes. 2004 Apr;53(4):955-62. doi: 10.2337/diabetes.53.4.955.
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• Krzystyniak A, Golab K, Witkowski P, Trzonkowski P. Islet cell transplant and the incorporation of Tregs. Curr Opin Organ Transplant. 2014 Dec;19(6):610-5. doi: 10.1097/MOT.0000000000000130.
• Pierini A, Iliopoulou BP, Peiris H, Perez-Cruz M, Baker J, Hsu K, Gu X, Zheng PP, Erkers T, Tang SW, Strober W, Alvarez M, Ring A, Velardi A, Negrin RS, Kim SK, Meyer EH. T cells expressing chimeric antigen receptor promote immune tolerance. JCI Insight. 2017 Oct 19;2(20):e92865. doi: 10.1172/jci.insight.92865.
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• Meyer EH, Laport G, Xie BJ, MacDonald K, Heydari K, Sahaf B, Tang SW, Baker J, Armstrong R, Tate K, Tadisco C, Arai S, Johnston L, Lowsky R, Muffly L, Rezvani AR, Shizuru J, Weng WK, Sheehan K, Miklos D, Negrin RS. Transplantation of donor grafts with defined ratio of conventional and regulatory T cells in HLA-matched recipients. JCI Insight. 2019 May 16;4(10):e127244. doi: 10.1172/jci.insight.127244. eCollection 2019 May 16.
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• Bellacen K, Kalay N, Ozeri E, Shahaf G, Lewis EC. Revascularization of pancreatic islet allografts is enhanced by alpha-1-antitrypsin under anti-inflammatory conditions. Cell Transplant. 2013;22(11):2119-33. doi: 10.3727/096368912X657701. Epub 2012 Oct 8.
• Hubbard RC, Sellers S, Czerski D, Stephens L, Crystal RG. Biochemical efficacy and safety of monthly augmentation therapy for alpha 1-antitrypsin deficiency. JAMA. 1988 Sep 2;260(9):1259-64.
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• Weir GC, Ehlers MR, Harris KM, Kanaparthi S, Long A, Phippard D, Weiner LJ, Jepson B, McNamara JG, Koulmanda M, Strom TB; ITN RETAIN Study Team. Alpha-1 antitrypsin treatment of new-onset type 1 diabetes: An open-label, phase I clinical trial (RETAIN) to assess safety and pharmacokinetics. Pediatr Diabetes. 2018 Aug;19(5):945-954. doi: 10.1111/pedi.12660. Epub 2018 May 7.
• Koulmanda M, Bhasin M, Fan Z, Hanidziar D, Goel N, Putheti P, Movahedi B, Libermann TA, Strom TB. Alpha 1-antitrypsin reduces inflammation and enhances mouse pancreatic islet transplant survival. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15443-8. doi: 10.1073/pnas.1018366109. Epub 2012 Sep 4.
• Wang J, Sun Z, Gou W, Adams DB, Cui W, Morgan KA, Strange C, Wang H. alpha-1 Antitrypsin Enhances Islet Engraftment by Suppression of Instant Blood-Mediated Inflammatory Reaction. Diabetes. 2017 Apr;66(4):970-980. doi: 10.2337/db16-1036. Epub 2017 Jan 9.
• Berger M, Liu M, Uknis ME, Koulmanda M. Alpha-1-antitrypsin in cell and organ transplantation. Am J Transplant. 2018 Jul;18(7):1589-1595. doi: 10.1111/ajt.14756. Epub 2018 Apr 24.
• Taylor GD, Kirkland T, Lakey J, Rajotte R, Warnock GL. Bacteremia due to transplantation of contaminated cryopreserved pancreatic islets. Cell Transplant. 1994 Jan-Feb;3(1):103-6. doi: 10.1177/096368979400300114.
• Lloveras J, Farney AC, Sutherland DE, Wahoff D, Field J, Gores PF. Significance of contaminated islet preparations in clinical islet transplantation. Transplant Proc. 1994 Apr;26(2):579-80. No abstract available.
• Rickels MR, Kamoun M, Kearns J, Markmann JF, Naji A. Evidence for allograft rejection in an islet transplant recipient and effect on beta-cell secretory capacity. J Clin Endocrinol Metab. 2007 Jul;92(7):2410-4. doi: 10.1210/jc.2007-0172. Epub 2007 May 8.
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• Terasaki PI, Ozawa M, Castro R. Four-year follow-up of a prospective trial of HLA and MICA antibodies on kidney graft survival. Am J Transplant. 2007 Feb;7(2):408-15. doi: 10.1111/j.1600-6143.2006.01644.x. Epub 2007 Jan 4.
• Ramsay RC, Goetz FC, Sutherland DE, Mauer SM, Robison LL, Cantrill HL, Knobloch WH, Najarian JS. Progression of diabetic retinopathy after pancreas transplantation for insulin-dependent diabetes mellitus. N Engl J Med. 1988 Jan 28;318(4):208-14. doi: 10.1056/NEJM198801283180403.
• Hirshberg B, Rother KI, Digon BJ 3rd, Lee J, Gaglia JL, Hines K, Read EJ, Chang R, Wood BJ, Harlan DM. Benefits and risks of solitary islet transplantation for type 1 diabetes using steroid-sparing immunosuppression: the National Institutes of Health experience. Diabetes Care. 2003 Dec;26(12):3288-95. doi: 10.2337/diacare.26.12.3288.
• Ryan EA, Lakey JR, Paty BW, Imes S, Korbutt GS, Kneteman NM, Bigam D, Rajotte RV, Shapiro AM. Successful islet transplantation: continued insulin reserve provides long-term glycemic control. Diabetes. 2002 Jul;51(7):2148-57. doi: 10.2337/diabetes.51.7.2148.
• Ryan EA, Paty BW, Senior PA, Shapiro AM. Risks and side effects of islet transplantation. Curr Diab Rep. 2004 Aug;4(4):304-9. doi: 10.1007/s11892-004-0083-8.
• Froud T, Yrizarry JM, Alejandro R, Ricordi C. Use of D-STAT to prevent bleeding following percutaneous transhepatic intraportal islet transplantation. Cell Transplant. 2004;13(1):55-9. doi: 10.3727/000000004772664897. Erratum In: Cell Transplant. 2004;13(4):475.
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• Manciu N, Beebe DS, Tran P, Gruessner R, Sutherland DE, Belani KG. Total pancreatectomy with islet cell autotransplantation: anesthetic implications. J Clin Anesth. 1999 Nov;11(7):576-82. doi: 10.1016/s0952-8180(99)00100-2.
• Froberg MK, Leone JP, Jessurun J, Sutherland DE. Fatal disseminated intravascular coagulation after autologous islet transplantation. Hum Pathol. 1997 Nov;28(11):1295-8. doi: 10.1016/s0046-8177(97)90204-5.
• Mehigan DG, Bell WR, Zuidema GD, Eggleston JC, Cameron JL. Disseminated intravascular coagulation and portal hypertension following pancreatic islet autotransplantation. Ann Surg. 1980 Mar;191(3):287-93. doi: 10.1097/00000658-198003000-00006.
• Mittal VK, Toledo-Pereyra LH, Sharma M, Ramaswamy K, Puri VK, Cortez JA, Gordon D. Acute portal hypertension and disseminated intravascular coagulation following pancreatic islet autotransplantation after subtotal pancreatectomy. Transplantation. 1981 Apr;31(4):302-4. No abstract available.

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2023
• Primary Completion (Estimated): May 1, 2025
• Study Completion (Estimated): May 1, 2028

Study Registration Dates

• First Submitted: June 14, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): August 3, 2023

Study Record Updates

• Last Update Posted (Actual): August 21, 2023
• Last Update Submitted That Met QC Criteria: August 18, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Death
• Other Study ID Numbers: 58350

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: No