Stem Cell Infusion for Kidney Transplant Tolerance
Recruiting in Palo Alto (17 mi)
Overseen byJeffrey Veale, MD
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: University of California, Los Angeles
Must not be taking: Immunotherapy, Immunomodulatory agents
Disqualifiers: Malignancy, Infection, Autoimmune, others
No Placebo Group
Approved in 2 Jurisdictions
Trial Summary
What is the purpose of this trial?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determine if patients with a pre-existing, well-functioning kidney transplant from a HLA-identical living donor can be withdrawn from immunosuppressive medications without compromising allograft function through hematopoietic stem cell (HPSC) infusion from the same donor.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).
Will I have to stop taking my current medications?
The trial aims to see if participants can stop taking their immunosuppressive medications after receiving a stem cell infusion. However, the protocol does not specify if you need to stop other medications, so it's best to discuss this with the trial team.
What data supports the effectiveness of the treatment Hematopoietic Stem Cell Infusion for Kidney Transplant Tolerance?
Research shows that combining kidney and hematopoietic stem cell transplants from a matched donor can help the body accept the new kidney without needing lifelong medication to suppress the immune system. Studies have reported that this approach can promote immune tolerance, reducing the risk of organ rejection and other complications.
12345Is the infusion of donor-derived hematopoietic stem cells safe for kidney transplant patients?
In clinical trials, the infusion of donor-derived hematopoietic stem cells into kidney transplant recipients has been well tolerated, with no adverse effects observed.
14567How is the treatment Hematopoietic Stem Cell Infusion unique for kidney transplant patients?
Hematopoietic Stem Cell Infusion is unique because it aims to induce immune tolerance, potentially allowing kidney transplant patients to stop using immunosuppressive drugs. This treatment involves infusing stem cells from a donor to create a state of 'chimerism' (a mix of donor and recipient cells), which helps the body accept the new kidney without rejecting it.
148910Eligibility Criteria
Adults over 18 with a well-functioning kidney transplant from an HLA-identical living donor can join. They must have good physical function, heart and liver health, no major post-transplant complications or rejection history, and stable kidney function. Women of childbearing age must use contraception.Inclusion Criteria
My current kidney transplant has not been rejected.
Resides or is willing to stay within 3 hours distance from UCLA Medical Center by ground transportation for the first three to six months of the trial at the physician's discretion
I haven't had major issues like new cancer, infections, or rejection after my transplant.
+11 more
Exclusion Criteria
My donor is my identical twin.
I do not have any unmanaged ongoing illnesses.
I have received transplants for more than one organ.
+16 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Conditioning
Participants undergo a conditioning regimen with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) to optimize engraftment
2-4 weeks
Hematopoietic Stem Cell Infusion
Infusion of hematopoietic stem cells from the HLA-identical donor
1 day
Weaning of Immunosuppression
Weaning of tacrolimus begins at 6 months with a goal of drug discontinuation within 12 months if conditions are met
6-12 months
Follow-up
Participants are monitored for safety and effectiveness after treatment, including graft function and chimerism measurement
48 months
Participant Groups
The trial tests if patients can stop taking anti-rejection drugs after receiving stem cells from their kidney donor. It includes a conditioning regimen with total lymphoid irradiation and rabbit anti-thymocyte globulin before the stem cell infusion.
1Treatment groups
Experimental Treatment
Group I: Immune tolerance in HLA-identical kidney transplant recipientExperimental Treatment1 Intervention
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).
Hematopoietic Stem Cell Infusion is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Hematopoietic Stem Cell Infusion for:
- Induction of immune tolerance in kidney transplant recipients
🇪🇺 Approved in European Union as Hematopoietic Stem Cell Transplantation for:
- Treatment of various hematologic malignancies and nonmalignant diseases
- Induction of immune tolerance in organ transplant recipients
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
UCLALos Angeles, CA
Loading ...
Who Is Running the Clinical Trial?
University of California, Los AngelesLead Sponsor
References
Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. [2021]Inducing donor-specific tolerance in renal transplant patients could potentially prevent allograft rejection and calcineurin inhibitor nephrotoxicity. Combined kidney and hematopoietic stem cell transplant from an HLA-matched donor is an exploratory and promising therapy to induce immune tolerance. Investigation of molecular mechanisms involved in the disease is needed to understand the potential process of cell therapy and develop strategies to prevent this immunologic rejection.
Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed hematopoietic chimerism. [2021]Stem cells (SCs) with varying potentiality have the capacity to repair injured tissues. While promising animal data have been obtained, allogeneic SCs and their progeny are subject to immune-mediated rejection. Here, we review the potential of hematopoietic stem cells (HSCs) to promote immune tolerance to allogeneic and xenogeneic organs and tissues, to reverse autoimmunity, and to be used optimally to cure hematologic malignancies. We also review the mechanisms by which hematopoietic cell transplantation (HCT) can promote anti-tumor responses and establish donor-specific transplantation tolerance. We discuss the barriers to clinical translation of animal studies and describe some recent studies indicating how they can be overcome. The recent achievements of durable mixed chimerism across human leukocyte antigen barriers without graft-versus-host disease and of organ allograft tolerance through combined kidney and bone marrow transplantation suggest that the potential of this approach for use in the treatment of many human diseases may ultimately be realized.
Apheresis of Deceased Donors as a New Source of Mobilized Peripheral Blood Hematopoietic Stem Cells for Transplant Tolerance. [2023]Solid organ transplantation is the therapy of choice for many patients with end-stage organ failure; however, recipients must remain on lifelong immunosuppression, leaving them susceptible to infections and cancer. The study of transplant tolerance to prolong graft survival in the absence of immunosuppression has been restricted to recipients of living donor allografts; however, deceased donors significantly outnumber living donors. Mobilization of hematopoietic stem cells (HSCs) from the bone marrow to peripheral blood (PB) could allow PB-HSCs to be used to induce tolerance in deceased donor kidney recipients; however, a major concern is the well-known concomitant mobilization of immune cells into the liver.
Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. [2004]Many strategies for tolerance induction have been developed, because this is the major goal of clinical transplantation. One of the most effective and best-studied approaches has been based on the injection of hematopoietic cells derived from the donor bone marrow, to establish a state of microchimerism in the recipient. A subset of hematopoietic stem cells might be responsible for the tolerogenic properties. These CD34+ bone marrow stem cells can be isolated and safely injected into kidney transplant recipients. In the authors' clinical trial, no adverse effects were observed, and the infusion of donor CD34+ cells was well tolerated.
Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up. [2022]Immunosuppressive therapy after life-saving kidney transplantation increases the risk of infection, cardiovascular diseases, metabolic diseases, and cancer. To date, four centers (three in the USA and one in South Korea) have reported clinical tolerance trials in kidney transplantation. We performed the first Chinese clinical trial in which kidney transplantation was combined with donor hematopoietic stem cell (DHSC) infusion to induce tolerance. This study summarizes the 10-year follow-up results.
Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy. [2023]Haemopoietic stem cell transplant (HSCT) is a well-established treatment option for many haematologic immunologic and oncologic diseases, allowing the safe administration of high-dose chemotherapy. Increased risk of acute renal injury is associated with HSCT; however, the risk of chronic kidney injury in autologous HSCT remains unclear.
Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance. [2022]The present review updates the current status of basic, preclinical, and clinical research on donor hematopoietic stem cell infusion for allograft tolerance induction.
The quest for transplantation tolerance: have we finally sipped from the cup? [2021]New advances in achieving hematopoietic chimerism may facilitate immunological tolerance to kidney transplants.
Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings. [2022]Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).
Macrochimerism and clinical transplant tolerance. [2019]Current theory holds that macrochimerism is essential to the development of transplant tolerance. Hematopoietic cell transplantation from the solid organ donor is necessary to achieve macrochimerism. Over the last 10-20 years, trials of tolerance induction with combined kidney and hematopoietic cell transplantation have moved from the preclinical to the clinical arena. The achievement of macrochimerism in the clinical setting is challenging, and potentially toxic due to the conditioning regimen necessary to hematopoietic cell transplantation and due to the risk of graft-versus-host disease. There are differences in chimerism goals and methods of the three major clinical stage tolerance induction strategies in both HLA-matched and HLA-mismatched living donor kidney transplantation, with consequent differences in efficacy and safety. The Stanford protocol has proven efficacious in the induction of tolerance in HLA-matched kidney transplantation, allowing cessation of immunosuppressive drug therapy in 80% of study participants, with the safety profile of conventional transplantation. In HLA-mismatched transplantation, multi-lineage macrochimerism of over a year's duration can now be consistently achieved with the Stanford protocol, with complete withdrawal of immunosuppressive drug therapy during the second post-transplant year as the next experimental step and test of tolerance.