Retro-active Immunological Tolerance in Patients With Well-functioning Pre-existing HLA-identical Kidney Transplants

Phase 1

Recruiting

• Conditions: End Stage Kidney Disease; Kidney Transplant Failure and Rejection; Immunological Tolerance; Chronic Kidney Diseases
• Interventions: Combination Product: Conditioning and Stem cell infusion

• Registration Number: NCT05525507
• Lead Sponsor: University of California, Los Angeles

Brief Summary

The study seeks to determine if patients with a pre-existing, well-functioning kidney transplant from a HLA-identical living donor can be withdrawn from immunosuppressive medications without compromising allograft function through hematopoietic stem cell (HPSC) infusion from the same donor. HPSC infusion will be preceded by a conditioning regimen of total lymphoid irradiation (TLI) and rabbit anti-thymocyte globulin (rATG).

Detailed Description

Immunological tolerance through combined kidney and HPSC transplant has been demonstrated at few centers of excellence within the United States. The ultimate aim of these protocols is to liberate patients from lifelong immunosuppression. Thus far, protocols have been limited to HLA-identical donor recipient pairs, undergoing simultaneous kidney transplant and HPSC infusion. In all protocols, the recipient undergoes a conditioning regimen to optimize engraftment. Our protocol employs a conditioning regimen of TLI and ATG.

There are many more patients with pre-existing well-functioning HLA-identical kidney transplants than those who present de novo for participation in tolerance trials. Despite this, post hoc tolerance induction through HPSC infusion in patients with a pre-existing kidney transplant has not yet been performed. Given the demonstrated success of tolerance protocols in simultaneous haploidentical kidney and HPSC transplant, the next logical step is to demonstrate that tolerance can be induced in the much greater subset of patients with pre-existing kidney transplants.

This study employs an established protocol for immunological tolerance induction in patients with a pre-existing, well- functioning kidney transplant from their haploidentical donor. These patients will undergo a conditioning with TLI and ATG, followed by infusion of HPSC from the same HLA-identical donor that provided the original kidney. The Investigators call this process "retroactive tolerance induction."

The investigators will evaluate whether recipients can be withdrawn from immunosuppressive drugs without compromising allograft function. At serial time points, (1) graft function will be monitored, and (2) chimerism will be measured in recipient whole blood and white blood cell subsets. Weaning of tacrolimus will begin at 6 months, with a goal of drug discontinuation within 12 months if the following conditions are met: (1) chimerism (defined as ≥1% donor type cells among the T cells, B cells, NK cells, and granulocytes) is detectable for at least 180 days after CD34+ and CD3+ cell infusion, (2) stable graft function (defined as eGFR \>30 mL/min and no greater than sustained 30% change over 3 months from baseline) without clinical rejection episodes is maintained, and (3) there is no evidence of graft vs. host disease (GVHD).

Study Timeline

• Study First Submitted: 2022-08-30
• Study First Submitted QC: 2022-08-31
• Study First Posted: 2022-09-01
• Study Start: 2022-12-21
• Status Verified: 2024-02
• Last Update Submitted: 2024-02-22
• Last Update Posted: 2024-02-26
• Primary Completion: 2026-09
• Study Completion: 2026-09

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 10

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Immune tolerance in HLA-identical kidney transplant recipient	Conditioning and Stem cell infusion	We seek to establish immunological tolerance in patients with a pre-existing, well- functioning kidney transplant from an HLA-identical donor. Patients will undergo conditioning with TLI and ATG, followed by infusion of hematopoietic stem cells from the same donor . We will evaluate whether recipients can be withdrawn from immunosuppressive drugs without compromising allograft function. At serial time points, graft function will be monitored, and chimerism will be measured. Weaning of tacrolimus will begin at 6 months, with a goal of drug discontinuation within 12 months if the following conditions are met: (1) chimerism (defined as ≥1% donor type cells among the T cells, B cells, NK cells, and granulocytes) is detectable for at least 180 days, (2) stable graft function (defined as eGFR \>30 mL/min and no greater than sustained 30% change over 3 months from baseline) without clinical rejection episodes is maintained, and (3) no evidence of graft vs. host disease (GVHD).

Primary Outcome Measures

Name	Time	Method
Incidence of successful discontinuation of immunosuppression	12 months	To determine whether patients with pre-existing kidney transplants from a haploidentical living donor can be withdrawn from immunosuppressive drugs while maintaining stable graft function within 12 months of hematopoietic stem cell infusion from the same HLA-identical living donor, preceded by conditioning with TLI and ATG.

Secondary Outcome Measures

Name	Time	Method
Graft survival	24 months	To determine graft survival within the first 24 months post-HPSC infusion.
Incidence of allograft rejection	48 months	To determine the percentage of subjects with graft rejection within 48 months post-HPSC infusion defined as (1) meets Banff criteria for rejection on biopsy performed to confirm clinical suspicion of rejection or (2) clinical suspicion of rejection demonstrating response to corticosteroids in absence of biopsy when confirmatory biopsy contraindicated or declined.

Trial Locations

Locations (1)

UCLA; 🇺🇸 Los Angeles, California, United States