Stem Cell Infusion for Kidney Transplant Tolerance

Overseen By Ruth Wynne Jones

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of California, Los Angeles

Must not be taking: Immunotherapy, Immunomodulatory agents

Disqualifiers: Malignancy, Infection, Autoimmune, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if individuals with a well-functioning kidney transplant from a perfectly matched living donor can safely stop taking immune-suppressing drugs without harming the kidney. The process involves infusing stem cells (Hematopoietic Stem Cell Infusion) from the same donor after preparing the body with specific treatments. Ideal participants have received a kidney transplant from a matching donor within the last 3 months to 5 years, maintain stable kidney health, and have no history of complications like rejection or infections. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative approach.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that giving stem cells to kidney transplant patients is generally safe. In earlier studies, patients who received these stem cells handled them well, with no unexpected health problems reported. This indicates that the stem cell treatment is well-tolerated. However, each person's experience may vary, and ongoing research aims to confirm its safety and effectiveness. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatment?

Unlike the standard of care for kidney transplant recipients, which typically involves long-term use of immunosuppressive drugs to prevent organ rejection, the hematopoietic stem cell infusion approach aims to achieve immune tolerance. This treatment is unique because it involves infusing stem cells from the kidney donor into the recipient, potentially allowing the recipient's immune system to accept the transplant without ongoing heavy medication. Researchers are excited about this treatment because, if successful, it could reduce or eliminate the need for immunosuppressants, which often come with significant side effects, and improve the quality of life for transplant patients.

What evidence suggests that hematopoietic stem cell infusion might be an effective treatment for kidney transplant tolerance?

This trial will evaluate hematopoietic stem cell infusion to help kidney transplant patients reduce or even stop taking anti-rejection drugs without harming the new kidney. Participants will receive stem cells from their HLA-identical kidney donor, along with conditioning treatments of Total Lymphoid Irradiation and Rabbit Anti-Thymocyte Globulin. Research has shown that these special blood stem cells can lead to long-term kidney health by helping the body accept the new kidney. Evidence from clinical trials suggests this approach is safe and effective in reducing medication reliance for kidney transplant patients. Overall, using these stem cells shows promise in maintaining a transplanted kidney's health with fewer drugs. ^{1 3 5 6 7}

Who Is on the Research Team?

Jeffrey Veale, MD

Principal Investigator

Professor of Urology

Are You a Good Fit for This Trial?

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.

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Hematopoietic Stem Cell Infusion
• Rabbit Anti-Thymocyte Globulin
• Total Lymphoid Irradiation

Trial Overview 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.

How Is the Trial Designed?

Group I: Immune tolerance in HLA-identical kidney transplant recipient Experimental Treatment 1 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

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Published Research Related to This Trial

In a study involving nine patients, the infusion of donor hematopoietic stem cells after kidney transplantation led to significant changes in protein profiles, suggesting a potential mechanism for inducing immune tolerance and preventing organ rejection.

The analysis revealed that proteins related to inflammation and the complement system were downregulated in patients receiving combined kidney and stem cell transplants, indicating a shift towards a more tolerant immune response compared to those with kidney transplants alone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. Wu, D., Qi, G., Wang, X., et al.[2021]

Injecting donor-derived CD34+ bone marrow stem cells into kidney transplant recipients can help induce tolerance, which is a key goal in transplantation.

In a clinical trial, the infusion of these cells was found to be safe and well tolerated, with no adverse effects reported, highlighting their potential for improving transplant outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. De Pauw, L., Toungouz, M., Goldman, M.[2004]

The Stanford protocol for tolerance induction in HLA-matched kidney transplantation has shown a high success rate, allowing 80% of participants to stop immunosuppressive drugs while maintaining a safety profile similar to conventional transplantation.

In HLA-mismatched kidney transplants, the Stanford protocol has successfully achieved multi-lineage macrochimerism for over a year, paving the way for future studies on complete withdrawal of immunosuppressive therapy in the second year post-transplant.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Macrochimerism and clinical transplant tolerance. Scandling, JD., Busque, S., Lowsky, R., et al.[2019]

In a study of 139 patients who underwent autologous stem cell transplantation, there was a significant decline in kidney function over 24 months, with the mean estimated glomerular filtration rate (eGFR) dropping from 80.62 to 71.54 mL/min.

The incidence of chronic renal injury increased from 12% to 38% within two years post-transplant, with older age and previous acute kidney injury identified as key risk factors for developing chronic kidney disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Incidence of chronic renal injury in patients undergoing autologous stem cell transplant therapy. Dawson, C., Palfreyman, E., Parisotto, R., et al.[2023]

Hematopoietic stem cells (HSCs) have the potential to promote immune tolerance for transplanted organs and tissues, which could help prevent rejection and improve outcomes in organ transplantation.

Recent studies have shown success in achieving durable mixed chimerism and organ allograft tolerance without causing graft-versus-host disease, indicating a promising pathway for treating various human diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Manipulating the immune system for anti-tumor responses and transplant tolerance via mixed hematopoietic chimerism. Gibbons, C., Sykes, M.[2021]

Recent advancements in achieving hematopoietic chimerism could improve the chances of developing immunological tolerance in kidney transplant recipients.

This approach may lead to better transplant outcomes by reducing the risk of organ rejection, although specific study details and participant numbers are not provided.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The quest for transplantation tolerance: have we finally sipped from the cup? Markmann, JF., Kawai, T.[2021]

This study reports the successful induction of immunological tolerance in three patients who received a kidney and hematopoietic stem cell transplant from HLA-identical siblings, with all patients remaining off immunosuppression for up to 4 years without rejection or graft-versus-host disease.

The approach demonstrated not only the feasibility of achieving tolerance but also maintained the patients' immune responses, as evidenced by their strong reactions to the mRNA COVID-19 vaccine, indicating a preserved ability to respond to infections.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings. Fehr, T., Hübel, K., de Rougemont, O., et al.[2022]

Donor hematopoietic stem cell infusion has been shown to induce allograft tolerance in kidney transplantation, allowing for successful transplants even with mismatched human leukocyte antigens.

Recent studies in animals, including swine, have demonstrated that durable mixed chimerism can lead to tolerance of complex tissue allografts, suggesting potential for broader applications in clinical transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell infusion/transplantation for induction of allograft tolerance. Granados, JM., Benichou, G., Kawai, T.[2022]

In a 10-year follow-up study of 11 kidney transplant recipients in China, the combination of donor hematopoietic stem cell (DHSC) infusion and total lymphoid irradiation (TLI) successfully induced immune tolerance, allowing for reduced immunosuppressive therapy while maintaining stable kidney function in most patients.

The protocol demonstrated safety, as none of the recipients developed myelosuppression or graft-versus-host disease (GVHD), and the risk of infection did not increase, highlighting the potential for this approach to improve long-term outcomes in kidney transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tolerance induction with donor hematopoietic stem cell infusion in kidney transplantation: a single-center experience in China with a 10-year follow-up. Wang, X., Yang, C., Hu, L., et al.[2022]

Hematopoietic stem cells (HSCs) can be successfully mobilized from the peripheral blood of deceased organ donors using a combination of granulocyte colony-stimulating factor and plerixafor, which may help induce transplant tolerance without the need for lifelong immunosuppression.

Importantly, this mobilization did not lead to increased immune cell trafficking into the liver, suggesting that this method could be safely applied in deceased donor kidney transplantation without compromising liver function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Apheresis of Deceased Donors as a New Source of Mobilized Peripheral Blood Hematopoietic Stem Cells for Transplant Tolerance. Sosa, RA., Mone, T., Naini, BV., et al.[2023]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7723571/

Tolerance induction with donor hematopoietic stem cell ... Our immune tolerance induction protocol, which used DHSC infusion and TLI, achieved low dose immunosuppression with long-term stable kidney allograft survival ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S0955470X23000460

Review article Hematopoietic cell-based and non- ... The purpose of this paper is to review the safety and efficacy of immune tolerance induction strategies in living-donor kidney transplantation, both chimerism- ...

3. clinicaltrials.gov clinicaltrials.gov/study/NCT02176434?term=AREA%5BConditionSearch%5D(Kidney%20Diseases)%20AND%20AREA%5BBasicSearch%5D(stem%20cell)%20AND%20AREA%5BOverallStatus%5D(RECRUITING)&rank=1

NCT02176434 | Pilot Feasibility Study of Combined Kidney ... This pilot study of combined kidney and hematopoietic stem cell transplantation attempts to establish a protocol to induce immunological tolerance as a new ...

4. withpower.com withpower.com/trial/phase-1-kidney-diseases-8-2022-dbe85

Stem Cell Infusion for Kidney Transplant Tolerance In clinical trials, the infusion of donor-derived hematopoietic stem cells into kidney transplant recipients has been well tolerated, with no adverse effects ...

5. translational-medicine.biomedcentral.com translational-medicine.biomedcentral.com/articles/10.1186/1479-5876-10-182

Hematopoietic stem cell transplantation induces immunologic ... Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT05525507

Retro-active Immunological Tolerance in Patients With Well ... We seek to establish immunological tolerance in patients with a pre-existing, well- functioning kidney transplant from an HLA-identical donor. Patients will ...

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1600613525000735

Induction of immune tolerance in living related human ... Tolerance has been induced occasionally when a kidney transplant recipient receives a bone marrow transplant or hematopoietic stem cell transplant (HSCT) from ...