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

Living Donor Kidney Transplantation Clinical Trial

Official title:

Phase 1 Study of Total Lymphoid Irradiation, Total Body Irradiation, Anti-Thymocyte Globulin and Purified Donor CD34+, T-cell and Recipient T Regulatory Cell Transfusion in Human Leukocyte Antigen Mismatched Living Donor Kidney Transplantation

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03943238
• Other study ID #: 50540
• Status: Recruiting
• Phase: Phase 1
• Start date: February 1, 2020
• Est. completion date: October 1, 2024

Study information

• Verified date: November 2023
• Source: Stanford University
• Contact: Kevin Ly, BS
• Phone: 650-497-6057
• Email: kevinly[@]stanford.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 22
• Est. completion date: October 1, 2024
• Est. primary completion date: August 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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

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.

Related Conditions & MeSH terms

• Living Donor Kidney Transplantation

Intervention

Biological:
• Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs
Living donor kidney transplant recipients will receive after a preparatory regimen of total lymphoid irradiation, total body irradiation and anti-thymocyte globulin an infusion of purified donor CD34+ of >10 x10^6 cells /Kg, 100 x 10^6 donor T cell/ Kg and and an escalated dose of recipient Tregs starting at 25 x10^6/Kg.

Locations

Country	Name	City	State
United States	Nothwestern University	Chicago	Illinois
United States	Stanford University	Palo Alto	California

Sponsors (3)

Lead Sponsor	Collaborator
Stanford University	California Institute for Regenerative Medicine (CIRM), Northwestern University

Country where clinical trial is conducted

United States, 

References & Publications (5)

Ildstad ST, Leventhal J, Wen Y, Yolcu E. Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance. Chimerism. 2015 Apr 3;6(1-2):33-9. doi: 10.1080/19381956.2015.1130780. Epub 2016 Jan 8. — View Citation

Leventhal JR, Ildstad ST. Tolerance induction in HLA disparate living donor kidney transplantation by facilitating cell-enriched donor stem cell Infusion: The importance of durable chimerism. Hum Immunol. 2018 May;79(5):272-276. doi: 10.1016/j.humimm.2018.01.007. Epub 2018 Mar 2. — View Citation

Scandling JD, Busque S, Lowsky R, Shizuru J, Shori A, Engleman E, Jensen K, Strober S. Macrochimerism and clinical transplant tolerance. Hum Immunol. 2018 May;79(5):266-271. doi: 10.1016/j.humimm.2018.01.002. Epub 2018 Jan 9. — View Citation

Scandling JD, Busque S, Shizuru JA, Engleman EG, Strober S. Induced immune tolerance for kidney transplantation. N Engl J Med. 2011 Oct 6;365(14):1359-60. doi: 10.1056/NEJMc1107841. No abstract available. — View Citation

Scandling JD, Busque S, Shizuru JA, Lowsky R, Hoppe R, Dejbakhsh-Jones S, Jensen K, Shori A, Strober JA, Lavori P, Turnbull BB, Engleman EG, Strober S. Chimerism, graft survival, and withdrawal of immunosuppressive drugs in HLA matched and mismatched patients after living donor kidney and hematopoietic cell transplantation. Am J Transplant. 2015 Mar;15(3):695-704. doi: 10.1111/ajt.13091. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Count of participants with sustained mixed chimerism of >25% at 18 months	Chimerism is defined as the co-existence of the immune cell from both the donor and the recipient.	Month 18
Primary	Count of participants able to withdraw from immunosuppressive drugs without evidence of rejection at 18 months		Month 18
Secondary	Count of participants with adverse events associated with the infusion of the Tregs cell product		up to 2 years
Secondary	Count of participants with bacterial, viral, or fungal infections		up to 2 years