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

NCT ID: NCT03943238

Last Updated: 2023-11-22

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE1
• Total Enrollment: 22 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2020-02-01
• Study Completion Date: 2024-10-01

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.

Conditions

Living Donor Kidney Transplantation

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Combined kidney/stem cell transplants and recipient's Tregs

Preparatory regimen including TLI, TBI, ATG after kidney transplantation followed by infusion of donor CD34+, T cell and recipient Tregs

Group Type: EXPERIMENTAL

Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs

Intervention Type: BIOLOGICAL

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.

Interventions

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.

Intervention Type: BIOLOGICAL

Eligibility Criteria

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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

California Institute for Regenerative Medicine (CIRM)

OTHER

Sponsor Role: collaborator

Northwestern University

OTHER

Sponsor Role: collaborator

Stanford University

OTHER

Sponsor Role: lead

Responsible Party

Everett Meyer

Principal Investigator

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Everett Meyer, MD

Role: STUDY_DIRECTOR

Stanford University

Locations

Stanford University

Palo Alto, California, United States

Site Status: RECRUITING

Nothwestern University

Chicago, Illinois, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Kevin Ly, BS

Role: CONTACT

kevinly@stanford.edu

650-497-6057

Stephan Busque, MD

Role: CONTACT

sbusque@stanford.edu

650-498-6189

Facility Contacts

Renata Gilfanova

Role: primary

Rgilfan@stanford.edu

650-736-0245

Stephan Busque, MD

Role: backup

sbusque@stanford.edu

650-498-6189

Leah Goudy, RN

Role: primary

leah.goudy@northwestern.edu

312-694-0242

Joseph Leventhal, MD

Role: backup

jleventh@nm.org

312-695-8900

References

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.

Reference Type: BACKGROUND

PMID: 29409743 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 26745761 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 25693475 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21991976 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 29330112 (View on PubMed)

Other Identifiers

50540

Identifier Type: -

Identifier Source: org_study_id