TLI, TBI, ATG & Hematopoietic Stem Cell Transplantation and Recipient T Regs Therapy in Living Donor Kidney Transplantation

Phase 1

Recruiting

• Conditions: Living Donor Kidney Transplantation
• Interventions: Biological: Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs

• Registration Number: NCT03943238
• Lead Sponsor: Stanford University

Brief Summary

This study will determine whether a preparatory regimen including total lymphoid irradiation (TLI), total body irradiation (TBI), anti-thymocyte globulin (ATG) and infusion of the donor hematopoietic stem cells when given along with recipient regulatory T cells (Tregs) will allow for eventual discontinuation of anti-rejection drugs after living donor kidney transplantation.

Detailed Description

It has been demonstrated that hematopoietic mixed chimerism or the coexistence of both donor and recipient immune cells can lead to tolerance to the graft in absence of graft versus host disease (GVHD). The goal of this pilot study is to determine if recipients of living donor kidney transplant can be successfully withdraw from immunosuppressive drugs. The patients will receive a preparatory regimen consisting of TLI and a low single dose of TBI and ATG following their kidney transplantation. Two weeks later, they will receive purified hematopoietic stem cells (CD34+) and Tcells that have been collected 6 weeks prior from their kidney donor. Regulatory T cells (Tregs) that have been collected from the recipient prior to the transplantation and expanded in vitro will be infuse the following day to enhance the chance of engraftment of the donor bone marrow cells. If chimerism develops and persists, the immunosuppressive drug will be tapered and stop. Mycophenolate mofetil (MMF) will be stopped 12 months after transplantation and if the chimerism remains stable, tacrolimus will be stopped 6 months later. The dose of Tregs will be escalated if the % of donor chimerism is not at least 25% during the first 60 days.

Study Timeline

• Study First Submitted: 2019-05-07
• Study First Submitted QC: 2019-05-07
• Study First Posted: 2019-05-09
• Study Start: 2020-02-01
• Status Verified: 2023-11
• Last Update Submitted: 2023-11-20
• Last Update Posted: 2023-11-22
• Primary Completion: 2024-08-01
• Study Completion: 2024-10-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 22

Inclusion Criteria

1. All consenting adults who are 18 to 65 years, living donor renal transplant recipients at Stanford University Medical Center or Northwestern Medicine who have a haplotype matched (minimum single Human Leukocyte Antigen - DR locus (HLA-DR) and HLA-A or B match) living related or unrelated donor.
2. Patients who agree to participate in the study and sign an Informed Consent.
3. Patients who have no known contraindication to administration of rabbit ATG or radiation.
4. Males and females of reproductive potential who agree to practice a reliable form of contraception for at least 1 year posttransplant

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Exclusion Criteria

1. Previous treatment with rabbit ATG or a known allergy to rabbit proteins.
2. History of malignancy with the exception of non-melanoma skin malignancies.
3. Pregnant women or nursing mothers.
4. Serological evidence of HIV, Hepatitis B surface antigen positive (HBsAg+), or Hepatitis C infection. Epstein Barr Virus (EBV) positive to EBV negative.
5. Leukopenia (with a white blood cell count < 3000/mm3) or thrombocytopenia (with a platelet count < 100,000/mm3).
6. Panel Reactive Antibody (PRA) greater than 80% or demonstration of historic and/or current donor specific antibody (DSA)
7. Prior organ transplantation
8. High risk of primary kidney disease recurrence
9. Advanced coronary or vascular disease.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Combined kidney/stem cell transplants and recipient's Tregs	Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs	Preparatory regimen including TLI, TBI, ATG after kidney transplantation followed by infusion of donor CD34+, T cell and recipient Tregs

Primary Outcome Measures

Name	Time	Method
Count of participants with sustained mixed chimerism of >25% at 18 months	Month 18	Chimerism is defined as the co-existence of the immune cell from both the donor and the recipient.
Count of participants able to withdraw from immunosuppressive drugs without evidence of rejection at 18 months	Month 18

Secondary Outcome Measures

Name	Time	Method
Count of participants with adverse events associated with the infusion of the Tregs cell product	up to 2 years
Count of participants with bacterial, viral, or fungal infections	up to 2 years

Trial Locations

Locations (2)

Stanford University; 🇺🇸 Palo Alto, California, United States

Nothwestern University; 🇺🇸 Chicago, Illinois, United States