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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Living Donor Kidney Transplantation
• Intervention / Treatment: Biological: Infusion of Donor Hematopoetic Stem Cells and Recipient Tregs

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 Type: Interventional
• Enrollment (Estimated): 22
• 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
      • Recruiting
      • Stanford University
      • Principal Investigator: Stephan Busque, MD
      • Contact: Stephan Busque, MD; Phone Number: 650-498-6189; Email: sbusque@stanford.edu
      • Contact: Renata Gilfanova; Phone Number: 650-736-0245; Email: Rgilfan@stanford.edu
      • Principal Investigator: Everett Meyer, MD
      • Sub-Investigator: Richard Hoppe, MD
      • Sub-Investigator: John Scandling, MD
      • Sub-Investigator: Kent Jensen, PhD
      • Sub-Investigator: Colin Lenihan, MD
      • Sub-Investigator: Thomas Pham, MD
      • Sub-Investigator: Robert Lowsky, MD
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Nothwestern University
      • Contact: Leah Goudy, RN; Phone Number: 312-694-0242; Email: leah.goudy@northwestern.edu
      • Contact: Joseph Leventhal, MD; Phone Number: 312-695-8900; Email: jleventh@nm.org
      • Sub-Investigator: Jayesh Mehta, MD
      • Sub-Investigator: James Mathew, PhD
      • Sub-Investigator: Lorenzo Gallon, MD
      • Principal Investigator: Joseph Leventhal, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 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	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Count of participants able to withdraw from immunosuppressive drugs without evidence of rejection at 18 months		Month 18

Secondary Outcome Measures

Outcome Measure	Time Frame
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

Collaborators and Investigators

• Sponsor: Stanford University
• Collaborators: Northwestern University; California Institute for Regenerative Medicine (CIRM)
• Investigators: Study Director: Everett Meyer, MD, Stanford University

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start (Actual): February 1, 2020
• Primary Completion (Estimated): August 1, 2024
• Study Completion (Estimated): October 1, 2024

Study Registration Dates

• First Submitted: May 7, 2019
• First Submitted That Met QC Criteria: May 7, 2019
• First Posted (Actual): May 9, 2019

Study Record Updates

• Last Update Posted (Estimated): November 22, 2023
• Last Update Submitted That Met QC Criteria: November 20, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Stem cells; kidney transplant; Tregs; Immunological Tolerance
• Other Study ID Numbers: 50540

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