Hematopoietic Cell Transplantation for Immune Tolerance in Kidney Transplant Recipients
Recruiting in Palo Alto (17 mi)
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Stephan Busque
Disqualifiers: Malignancy, HIV, Hepatitis B/C, others
No Placebo Group
Approved in 1 Jurisdiction
Trial Summary
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Globulin (rATG) and an HLA matched donor hematopoietic progenitor cell infusion such that their drugs are successfully withdrawn while maintaining normal renal function.
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.
12345Is 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.
678910How 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.
1112131415Eligibility 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.
+3 more
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.
+4 more
Trial 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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Immune tolerance, Kidney transplantationExperimental Treatment2 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Stanford University Medical CenterPalo Alto, CA
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Who Is Running the Clinical Trial?
Stephan BusqueLead Sponsor
References
Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan. [2013]Among the dimethanesulfonates, busulfan, in combination with other alkylating agents or nucleoside analogues, is the cornerstone of high-dose chemotherapy. It is used, and followed hematopoietic stem cell transplantation, for the treatment of various hematologic malignancies and immunodeficiencies. Treosulfan, which is a hydrophilic analogue of busulfan, was the first dimethanesufonate registered for the treatment of ovarian cancer. Recently, treosulfan has been investigated for the treatment of hematologic malignancies in combination with the same second agents before hematopoietic stem cell transplantation.
Addition of treosulfan to a nonmyeloablative conditioning regimen results in enhanced chimerism and immunologic tolerance in an experimental allogeneic bone marrow transplant model. [2013]Treosulfan (L-threitol-1,4-bismethanesulfonate) is an alkylating agent with routine clinical application in the treatment of ovarian cancer. In this murine study we show that this drug also has the ability to deplete primitive hematopoietic stem cells in a dose-dependent manner as determined by the cobblestone area-forming cell assay and is similar to its parent compound busulfan. Because busulfan is frequently used as part of the conditioning regimen before stem cell transplantation, we investigated an alternative nonmyeloablative protocol in an allogeneic bone marrow transplantation model in which low-dose treosulfan was added to an immune-suppressive regimen consisting of T cell-depleting antibodies, fludarabine, and thymic irradiation. Although this treatment protocol produced minimal myelosuppression, the addition of treosulfan proved to be important for allowing stable multilineage and mixed chimerism in C57BL/6 recipients of major histocompatibility complex-mismatched B10.A bone marrow without evidence of graft-versus-host disease. Donor lymphocyte infusion performed at 10 weeks after bone marrow transplantation had the effect of transforming the state of mixed chimerism to full donor-type cells, again without evidence of graft-versus-host disease. Donor-specific immunologic tolerance in the mixed chimeric animals was indicated by the acceptance of donor-type and rejection of third-party skin grafts. Thus, low-dose treosulfan may be considered as a useful component of a truly nonmyeloablative conditioning protocol in providing for mixed hematopoietic chimerism and, consequently, in establishing a platform for adoptive immunotherapy.
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]To investigate whether we could create a radiation-free conditioning regimen to induce permanent mixed and multilineage chimerism and donor-specific tolerance, we treated recipient mice with anti-T-cell antibodies, varying and fractionated doses of Treosulfan and fully MHC disparate bone marrow cells. Treosulfan is mainly used in the treatment of ovarian cancer. It is a structural analog of busulfan, but it does not induce severe hepatotoxicity or veno-occlusive disease at or above the maximum tolerated dose, lacks significant nonhematological toxicity and has limited organ toxicity. We report here the successful induction of permanent mixed multilineage chimerism and donor-specific tolerance as was proven by skin transplantation and IFN-gamma ELISPOT. In conclusion, because of its lower nonhematological toxicity, compared with other myeloablative regimens (eg irradiation or busulfan admin- istration), Treosulfan could be a better candidate for conditioning to induce donor-specific allograft tolerance.
Treosulfan-based conditioning and hematopoietic cell transplantation for nonmalignant diseases: a prospective multicenter trial. [2021]Hematopoietic cell transplantation is an effective treatment for patients with nonmalignant diseases and for many is the only known cure. Conventional myeloablative regimens have been associated with unacceptably high early transplant-related mortality (TRM), particularly in patients with comorbid conditions. This prospective multicenter trial was designed to determine the safety and engraftment efficacy of treosulfan-based conditioning in patients with nonmalignant diseases. Thirty-one patients received HLA-matched related (n = 4) or unrelated (n = 27) grafts after conditioning with treosulfan (total dose, 42 g/m(2)), fludarabine (total dose, 150 mg/m(2)), ± thymoglobulin (6 mg/kg; n = 22). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and methotrexate. All patients engrafted. Day-100 TRM was 0%. With a median follow-up of 2 years, the 2-year survival was 90%. Three patients died of GVHD, recurrent hemophagocytic lymphohistiocytosis, and a surgical complication, respectively. The cumulative incidences of grades II to IV and III to IV acute GVHD at day 100 and chronic GVHD at 2 years were 62%, 10%, and 21%, respectively. Patients who received thymoglobulin had a significantly lower incidence of grades III to IV acute GVHD (0% versus 33%; P = .005). These results indicate that the combination of treosulfan, fludarabine, and thymoglobulin is effective at establishing donor engraftment with low toxicity and improved survival in patients with nonmalignant diseases and support the need for future disease-specific clinical trials.
Antileukaemic activity of treosulfan in xenografted human acute lymphoblastic leukaemias (ALL). [2019]Treosulfan (L-threitol-1,4-bis-methanesulphonate; Ovastat(R)) is a bifunctional alkylating drug indicated for the treatment of advanced ovarian carcinoma. Recent data revealed immunosuppressive characteristics and substantial haematopoietic stem cell toxicity after repeated dosing of mice. Therefore, treosulfan is considered to be an alternative conditioning agent to busulfan (for example) administered prior to allogeneic/autologous stem cell transplantation of patients with haematological malignancies. An antineoplastic activity for treosulfan has been previously shown in preclinical models of melanoma, breast, lung and renal-cell carcinomas. Here, in vivo antileukaemic activity of treosulfan is compared with the activity of equitoxic doses of cyclophosphamide or busulfan for the first time using human acute lymphoblastic leukaemia (ALL)-models of paediatric origin xenotransplanted into non-obese diabetic (NOD)/severe combined immunodeficient (SCID) mice. Treosulfan treatment achieved an optimum treated to control (T/C) value of 159% (survival time) against B-ALL-SCID 7 and a T/C value of 0% (tumour growth) against T-ALL-SCID 4 and proB-ALL-SCID 19, respectively. Complete regression of established subcutaneously (s.c.) growing nodules of ALL-SCID 4 and 19 was obvious and long-term survivors without tumour re-growth were observed. Equitoxic doses of busulfan (ALL-SCID 4, 7, 19) or cyclophosphamide (ALL-SCID 19) were less effective with regard to the numbers of complete regressions and the number of cured animals. Side-effects included myelotoxicity and a small reduction in body weight, but these were tolerable. Treosulfan can be considered a highly active antileukaemic drug whose corresponding clinical value is to be tested in appropriate protocols with leukaemic patients.
Impact of recipient statin treatment on graft-versus-host disease after allogeneic hematopoietic cell transplantation. [2022]We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had hematopoietic cell transplantation (HCT) from HLA-identical siblings (n = 630) or HLA-matched unrelated donors (n = 576) at a single institution between 2001 and 2007 for a correlation between recipient statin use and risk of graft-versus-host disease (GVHD). Among recipients with cyclosporine-based postgrafting immunosuppression (n = 821), statin use at the time of transplant (6%) was associated with a decreased risk of extensive chronic GVHD (cGVHD) (multivariate hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.4-1.0; P = .05) and an increased risk of recurrent malignancy (HR, 1.75; 95% CI, 1.0-3.0; P = .04). Recipient statin use, however, had no apparent impact on the risks of cGVHD and recurrent malignancy among recipients given tacrolimus-based immunosuppression (n = 385; 8% statin treated). Risks of acute GVHD, nonrelapse mortality, and overall mortality were not significantly affected by recipient statin use. Hence, recipient statin treatment at the time of allogeneic HCT may decrease the risk of cGVHD in patients with cyclosporine-based immunosuppression, but at the expense of a compromised graft-versus-tumor effect.
Clotrimazole troches induce supratherapeutic blood levels of sirolimus and tacrolimus in an allogeneic hematopoietic cell-transplant recipient resulting in acute kidney injury. [2017]Allogeneic hematopoietic cell transplantation is a potential curative treatment option for various malignant and nonmalignant hematologic disorders. Patients undergoing an allogeneic hematopoietic cell transplant are prescribed immune-suppressant therapies to facilitate hematopoietic donor-cell engraftment and prevent graft-versus-host disease. Drug-drug interactions may occur, owing to exposure to complex multidrug regimens with narrow therapeutic windows and high toxicity profiles. Here, we describe a unique case of a 65-year-old man with poor-risk acute myeloid leukemia who underwent a matched-sibling hematopoietic cell allograft. Sirolimus and tacrolimus were used for graft-versus-host disease prophylaxis. He developed oral thrush requiring treatment with clotrimazole troches, which subsequently resulted in serious renal toxicity attributed to supratherapeutic levels of sirolimus and tacrolimus. Patient renal function improved after temporarily holding both immune suppressants, and administering phenytoin to help induce sirolimus and tacrolimus metabolism. This case highlights sudden and serious toxicities that resulted from clotrimazole-sirolimus and clotrimazole-tacrolimus drug-drug interactions, even when administered topically.
Treatment of dyslipidemia in allogeneic hematopoietic stem cell transplant patients. [2018]As survival rates in allogeneic hematopoietic stem cell transplantation (HSCT) continue to improve, attention to long-term complications, including cardiovascular disease, becomes a major concern. Cardiovascular disease and dyslipidemia are a common, yet often overlooked occurrence post-HSCT that results in significant morbidity and mortality. Also, increasing evidence shows that several anti-hyperlipidemia medications, the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in particular, may have a role in modulating graft-versus-host disease (GVHD). However, factors such as drug-drug interactions, adverse effect profiles, and the relative efficacy in lowering cholesterol and triglyceride levels must be taken into account when choosing safe and effective lipid-lowering therapy in this setting. This review seeks to provide guidance to the clinician in the management of dyslipidemia in the allogeneic HSCT population, taking into account the recently published American College of Cardiology/American Heart Association guidelines on hyperlipidemia management, special considerations in this challenging population, and the evidence for each agent's potential role in modulating GVHD.
Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Using Tacrolimus/Sirolimus-based GvHD Prophylaxis: Impact of HLA Mismatch. [2023]While tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined.
The evolving role of statins in hematopoietic stem and progenitor cell transplantation. [2021]Allogeneic hematopoietic stem cell transplantation is the sole curative modality for a variety of malignant and benign hematological disorders. Despite advances in supportive care and transplant conditioning regimens graft-versus-host disease (GVHD), infectious complications and end organ toxicity remain the leading causes of transplant related mortality (TRM). Development of safe and effective strategies to mitigate these significant complications associated with HSCT, are urgently needed. Statins are lipid lowering drugs, which reduce cholesterol production by inhibiting HMG-CoA reductase, with a well defined toxicity profile. Statins have pleiotropic immunomodulatory effects which are relevant in the context of treating and preventing GVHD. In addition to GVHD statins may possess several other effects that might have clinical benefit in the setting of hematopoietic cell transplantation, such as treatment of bronchiolitis obliterans and antineoplastic activity. Herein we review the emerging role of statins in improving the outcomes of patients undergoing HSCT.
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.
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.
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).
Induction of Tolerance Towards Solid Organ Allografts Using Hematopoietic Cell Transplantation in Large Animal Models. [2022]The application of hematopoietic cell transplantation for induction of immune tolerance has been limited by toxicities associated with conditioning regimens and to graft-versus-host disease (GVHD). Decades of animal studies have culminated into sufficient control of these two problems, making immune tolerance a viable alternative to life-long application of immunosuppressive drugs to prevent allograft rejection.
Generation of Donor-specific T Regulatory Type 1 Cells From Patients on Dialysis for Cell Therapy After Kidney Transplantation. [2015]T regulatory type 1 (Tr1) cell-mediated induction of tolerance in preclinical models of transplantation is remarkably effective. The clinical application of such a therapy in patients on dialysis undergoing kidney transplantation should take into account the possible alterations of the immune system observed in these patients. Herein, we aimed at testing the ability to generate donor-specific Tr1 cell-enriched lymphocytes from patients on dialysis on the waiting list for kidney transplantation.