Hematopoietic Cell Transplantation for Immune Tolerance in Kidney Transplant Recipients

Overseen By STEPHAN BUSQUE, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Stephan Busque

Disqualifiers: Malignancy, HIV, Hepatitis B/C, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

25 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial aims to help patients stop taking their immunosuppressive drugs, so you may need to stop these medications as part of the study.

What data supports the effectiveness of the drug Treosulfan in the treatment of kidney transplant recipients?

Treosulfan has shown effectiveness in creating immune tolerance and stable donor cell integration in bone marrow transplant models, which suggests it could help kidney transplant recipients accept the new organ without severe immune reactions. Additionally, it has been effective in treating other conditions like ovarian cancer and leukemia, indicating its potential as a conditioning agent in transplants. ^{1 2 3 4 5}

Is hematopoietic cell transplantation generally safe for humans?

Hematopoietic cell transplantation has been used to treat various blood disorders, but it can have serious side effects, including graft-versus-host disease (a condition where the donor cells attack the recipient's body) and organ toxicity. Drug interactions during treatment can also lead to complications, such as kidney injury. While some medications like statins may help reduce certain risks, the procedure still carries significant safety concerns. ^{6 7 8 9 10}

How is the treatment Hematopoietic Cell Transplantation unique for kidney transplant recipients?

Hematopoietic Cell Transplantation is unique because it combines kidney and stem cell transplants from a matched donor to induce immune tolerance, potentially eliminating the need for lifelong immunosuppressive drugs and reducing the risk of organ rejection. ^{11 12 13 14 15}

What is the purpose of this trial?

The study will determine whether patients with functioning Human Leukocyte Antigen (HLA) matched kidney transplants for at least one year and who want to discontinue immunosuppressive drugs can be treated with Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.

Research Team

Samuel Md Strober, MD

Principal Investigator

Stanford University

Eligibility Criteria

Adults over 18 with a functioning kidney transplant from an HLA-matched sibling for at least one year, who wish to stop taking immunosuppressive drugs. Participants must have no history of rejection, agree to use reliable contraception, and their donor must also consent and meet criteria for stem cell donation.

Inclusion Criteria

Patients who agree to participate in the study and sign an Informed Consent

I agree to use birth control for 18 months after my transplant.

I am not allergic or sensitive to rabbit ATG or radiation treatments.

Exclusion Criteria

I have had cancer before, but not skin cancer.

I have had a kidney transplant rejected or my original kidney disease came back.

My kidney biopsy shows rejection, disease recurrence, or significant scarring.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Conditioning

Participants receive Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG) as part of the conditioning regimen

2 weeks

Stem Cell Transplantation

Participants receive an infusion of CD34+ and CD3+ cells from their transplant donors

1 day

Immunosuppressive Drug Adjustment

Immunosuppressive drugs are adjusted and monitored, with MMF tapered starting 6 months later and Tacrolimus potentially discontinued at 12 months

12 months

Follow-up

Participants are monitored for safety, chimerism, graft function, and potential discontinuation of immunosuppressive drugs

6 months to up to five years

Treatment Details

Interventions

• Hematopoietic Cell Transplantation
• Total Lymphoid Irradiation

Trial Overview The trial is testing if Total Lymphoid Irradiation (TLI) and rabbit Anti-Thymocyte Globulin (rATG), followed by an infusion of donor hematopoietic progenitor cells can allow patients to safely discontinue immunosuppressive medications while maintaining normal kidney function.

Participant Groups

Group I: Immune tolerance, Kidney transplantation Experimental Treatment 2 Interventions

Intervention: HLA matched living donor recipients of a functioning kidney transplant graft at one year will receive hematopoietic cell transplantation and Total lymphoid irradiation. The intervention is intended to induce immune tolerance such as to allow withdrawal of the immunosuppressive drugs. Immune tolerance is achieved through the development of donor/recipient mixed chimerism following combined kidney and hematopoietic stem cell transplantation from the living donor.

Hematopoietic Cell Transplantation is already approved in European Union for the following indications:

Approved in European Union as Trecondi for:

• Allogeneic haematopoietic stem cell transplantation for malignant and non-malignant diseases

Who Is Running the Clinical Trial?

Stephan Busque

Lead Sponsor

Trials

1

Recruited

30+

Findings from Research

Busulfan has a well-established role in high-dose chemotherapy for treating hematologic malignancies and has been extensively studied for over 30 years, providing a clear understanding of its efficacy and pharmacokinetics.

Treosulfan, a newer analogue of busulfan, shows promise in treating hematologic malignancies but requires further research to fully understand its complex metabolism and pharmacological activity, particularly its pharmacokinetics and pharmacodynamics in high-dose chemotherapy contexts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. Galaup, A., Paci, A.[2013]

Treosulfan, an alkylating agent used for ovarian cancer, effectively depletes primitive hematopoietic stem cells in a dose-dependent manner, similar to busulfan, making it a potential alternative for conditioning before stem cell transplantation.

In a murine model, low-dose treosulfan combined with an immune-suppressive regimen allowed for stable mixed chimerism and donor-specific tolerance without causing graft-versus-host disease, suggesting its utility in nonmyeloablative transplantation protocols.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. Ploemacher, RE., Johnson, KW., Rombouts, EJ., et al.[2013]

A radiation-free conditioning regimen using Treosulfan successfully induced permanent mixed multilineage chimerism and donor-specific tolerance in recipient mice, demonstrating its potential for safer transplantation protocols.

Treosulfan showed lower nonhematological toxicity compared to traditional myeloablative treatments like irradiation or busulfan, making it a promising candidate for conditioning in organ transplantation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. van Pel, M., van Breugel, DW., Vos, W., et al.[2013]

In a study involving 31 patients with nonmalignant diseases, a conditioning regimen using treosulfan and fludarabine resulted in 100% engraftment and a 0% early transplant-related mortality (TRM) at 100 days, indicating a safe and effective approach for hematopoietic cell transplantation.

The combination of treosulfan, fludarabine, and thymoglobulin led to a 90% survival rate over two years, with significantly lower rates of severe acute graft-versus-host disease (GVHD) in patients who received thymoglobulin, suggesting improved outcomes and reduced toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. Burroughs, LM., Nemecek, ER., Torgerson, TR., et al.[2021]

Treosulfan demonstrated significant antileukaemic activity in pediatric models of acute lymphoblastic leukaemia (ALL), achieving complete regression of tumors and long-term survival in treated mice, outperforming equitoxic doses of busulfan and cyclophosphamide.

While treosulfan caused some myelotoxicity and minor weight loss, these side effects were manageable, suggesting it could be a promising alternative conditioning agent for stem cell transplantation in patients with hematological malignancies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). Fichtner, I., Becker, M., Baumgart, J.[2019]

In a study of 1206 patients with hematologic malignancies who underwent hematopoietic cell transplantation, statin use at the time of transplant was linked to a reduced risk of extensive chronic graft-versus-host disease (cGVHD) in those receiving cyclosporine-based immunosuppression.

However, statin use was also associated with an increased risk of recurrent malignancy, suggesting that while statins may help reduce cGVHD, they could compromise the graft-versus-tumor effect.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. Rotta, M., Storer, BE., Storb, R., et al.[2022]

A 65-year-old man with acute myeloid leukemia experienced serious renal toxicity due to drug-drug interactions between clotrimazole and the immune suppressants sirolimus and tacrolimus, which were used to prevent graft-versus-host disease after his allogeneic hematopoietic cell transplant.

The patient's renal function improved after temporarily stopping the immune suppressants and using phenytoin to enhance the metabolism of sirolimus and tacrolimus, highlighting the importance of monitoring for potential interactions even with topical medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury. El-Asmar, J., Gonzalez, R., Bookout, R., et al.[2017]

Long-term complications like cardiovascular disease and dyslipidemia are significant concerns for patients after allogeneic hematopoietic stem cell transplantation (HSCT), impacting their overall health and survival rates.

Certain anti-hyperlipidemia medications, particularly statins, may help manage dyslipidemia and potentially modulate graft-versus-host disease (GVHD), but clinicians must consider drug interactions and side effects when selecting appropriate treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of dyslipidemia in allogeneic hematopoietic stem cell transplant patients. Marini, BL., Choi, SW., Byersdorfer, CA., et al.[2018]

Tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis showed a 5-year overall survival rate of 47.5% in a study of 482 patients who underwent unrelated donor hematopoietic cell transplantation, indicating its effectiveness in preventing acute GvHD.

Patients receiving transplants from mismatched unrelated donors (mMUD) had significantly worse overall survival (39.0% vs. 50.7%) and higher rates of nonrelapse mortality, suggesting that mMUD is a risk factor for poorer outcomes, potentially due to increased severity of chronic GvHD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Using Tacrolimus/Sirolimus-based GvHD Prophylaxis: Impact of HLA Mismatch. Al Malki, MM., Gendzekhadze, K., Yang, D., et al.[2023]

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative option for many blood disorders, but complications like graft-versus-host disease (GVHD) and infections are major causes of mortality after the procedure.

Statins, known for lowering cholesterol, may help reduce the risk of GVHD and improve overall outcomes in HSCT patients due to their immunomodulatory effects and potential benefits in treating other complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of statins in hematopoietic stem and progenitor cell transplantation. Hamadani, M., Craig, MD., Gibson, LF., et al.[2021]

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]

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]

Nonmyeloablative hematopoietic cell transplantation (HCT) has been shown to successfully induce immune tolerance in large animal models, reducing the risk of graft-versus-host disease (GVHD) and allowing for stable organ transplantation without the need for lifelong immunosuppressive drugs.

The successful transplantation of kidneys in MHC-mismatched nonhuman primates using nonmyeloablative HCT and monoclonal antibody immunosuppression suggests a promising approach for achieving tolerance in organ transplants, although further research is needed for other organ types like the heart and lungs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Induction of Tolerance Towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models. Graves, SS., Mathes, DW., Storb, R.[2022]

Tr1 cell-enriched lymphocytes can be generated from patients on dialysis awaiting kidney transplantation, but using total peripheral blood mononuclear cells (PBMCs) resulted in a low anergic phenotype, making them unsuitable for clinical use.

In contrast, using purified CD4(+) T cells from these patients produced a highly anergic donor-specific product, indicating that tailoring the generation protocol to the patients' immune profiles can enhance the efficacy of this therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation. Petrelli, A., Tresoldi, E., Mfarrej, BG., et al.[2015]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. [2013]

2. United States pubmed.ncbi.nlm.nih.gov

Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. [2013]

3. England pubmed.ncbi.nlm.nih.gov

Towards a myeloablative regimen with clinical potential: I. Treosulfan conditioning and bone marrow transplantation allow induction of donor-specific tolerance for skin grafts across full MHC barriers. [2013]

4. United States pubmed.ncbi.nlm.nih.gov

Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. [2021]

5. England pubmed.ncbi.nlm.nih.gov

Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). [2019]

6. United States pubmed.ncbi.nlm.nih.gov

Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. [2022]

7. Saudi Arabia pubmed.ncbi.nlm.nih.gov

Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury. [2017]

8. United States pubmed.ncbi.nlm.nih.gov

Treatment of dyslipidemia in allogeneic hematopoietic stem cell transplant patients. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Using Tacrolimus/Sirolimus-based GvHD Prophylaxis: Impact of HLA Mismatch. [2023]

10. United States pubmed.ncbi.nlm.nih.gov

The evolving role of statins in hematopoietic stem and progenitor cell transplantation. [2021]

11. England pubmed.ncbi.nlm.nih.gov

Hematopoietic stem cell transplantation induces immunologic tolerance in renal transplant patients via modulation of inflammatory and repair processes. [2021]

12. United States pubmed.ncbi.nlm.nih.gov

Infusion of donor-derived hematopoietic stem cells in organ transplantation: clinical data. [2004]

13. Switzerland pubmed.ncbi.nlm.nih.gov

Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings. [2022]

14. United States pubmed.ncbi.nlm.nih.gov

Induction of Tolerance Towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models. [2022]

15. United States pubmed.ncbi.nlm.nih.gov

Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation. [2015]