Bone marrow transplant to improve kidney transplant outcomes

Delayed Tolerance Through Mixed Chimerism

This study is testing if a bone marrow transplant can help kidney transplant patients keep their new kidney healthy without needing as much medication to suppress their immune system.

Quick facts

• Phase: Phase1; Phase2
• Study type: Interventional
• Enrollment: 20 (estimated)
• Ages: 18 Years to 65 Years
• Sex: All
• Sponsor: Massachusetts General Hospital (Academic / other)
• Drugs / interventions: Siplizumab, rituximab, fludarabine, Cyclophosphamide
• Locations: 1 site (Boston, Massachusetts)
• Trial ID: NCT05900401 on ClinicalTrials.gov

What this trial studies

This study investigates the safety and effectiveness of a bone marrow transplant in kidney transplant recipients to promote tolerance and protect the transplanted kidney from immune system attacks. Participants will undergo a conditioning regimen involving several medications, including rituximab and fludarabine, followed by the infusion of donor hematopoietic stem cells. The study aims to assess the potential for reducing or eliminating the need for immunosuppressive therapy after transplantation. Renal allograft biopsies will be performed to evaluate kidney function and the success of the intervention.

Who should consider this trial

Good fit: Ideal candidates include adults aged 18-65 who have received a kidney transplant and have good renal function without a history of rejection.

Not a fit: Patients with significant kidney dysfunction or those who have experienced rejection episodes may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could lead to improved kidney transplant outcomes and reduced reliance on lifelong immunosuppressive medications.

How similar studies have performed: While similar approaches have been explored, this specific combination of interventions is novel and has not been extensively tested in prior studies.

Eligibility criteria

Recipient Inclusion Criteria

1. Male or female 18-65 years of age.
2. Kidney transplant recipients from either LD or DD, with cryo-preserved HSCs available, good renal function (GFR\>60 ml/min/1.73m2), normal current allograft biopsy, and no history of documented rejection episodes.
3. First or second renal transplant.
4. Use of FDA-approved methods of contraception (those with less than a 3% failure rate) by all recipients from the time that study treatment begins until 104 weeks (24 months) after renal transplantation. (For further information on FDA- approved methods of contraception, see https://www.fda.gov/media/150299/download
5. Ability to understand and provide informed consent.
6. Negative COVID-19 test during screening and two days prior to HSC transplantation (HSCT).

Deceased Donor (DD)

1. Male or female 18-70 years of age.
2. Consent to donate vertebral bones is obtained from the donor family.
3. HSCs are successfully cryopreserved and saved \>2X106/kg (CD34+ cells) of the recipient.
4. Acceptable laboratory parameters (hematology in normal or near-normal range. Liver function \<2 times the upper limit of normal, and normal creatinine)
5. Negative for viral infection with HbsAg, HIV, HCV, or HTLV-1
6. Negative COVID-19 test at the time of HSC procurement.

Living Donor (LD)

1. Willingness to provide HSCs by leukapheresis or bone marrow aspiration.
2. Negative serologic pregnancy test for females of childbearing potential
3. Good general health as per conventional evaluation for kidney donation.
4. Acceptable laboratory parameters (hematology in normal or near normal range. Liver function \<2 times the upper limit of normal, and normal creatinine)
5. Negative for viral infection with HbsAg, HIV, HCV, or HTLV-1.
6. Cardiac/pulmonary function within normal limits (CXR, ECG).
7. Ability to understand and provide informed consent.
8. Meets standard institutional criteria for PBSC collection.
9. Negative COVID-19 test during screening and two days prior to PBSC collection.

Recipient Exclusion Criteria

1. ABO blood group-incompatible renal allograft.
2. Evidence of anti-HLA antibody (donor specific with an MFI \>1000) as assessed by routine methodology (Luminex)
3. Previous history of biopsy proven rejection.
4. Persistent Leukopenia (WBC less than 2,000/mm3) or thrombocytopenia (\<100,000/mm3).
5. Seropositivity for HIV-1, hepatitis B surface or core antigen, or hepatitis C virus (confirmed by hepatitis C virus RNA).
6. Active infection
7. Left ventricular ejection fraction \< 40% as determined by TTE or clinical evidence of heart failure.
8. Forced expiratory volume FEV1 or DLCO \< 50% of predicted.
9. Lactation or pregnancy.
10. History of cancer (following the American Transplant Society Guidelines)
11. Underlying renal disease etiology with high risk of disease recurrence in the transplanted kidney (such as focal segmental glomerulosclerosis). Autoimmune diseases such as Lupus and Thrombotic Thrombocytopenic Purpura.
12. Enrollment in other investigational drug studies within 30 days prior to enrollment.
13. Abnormal (\>2 times lab normal) values for (a) liver function chemistries (ALT, AST, AP), (b) bilirubin, (c) coagulation studies (PT, PTT), or any patients on chronic anticoagulation therapy.
14. Allergy or sensitivity to any component of Siplizumab, fludarabine, CP, tacrolimus, MMF or rituximab.
15. Any medical condition that the investigator deems incompatible with participation in the trial. This includes a history of alcohol abuse or illicit drug use/dependence.
16. Non-insulin dependent diabetes (NIDDM) without good blood glucose control (HbA1c\<7). Severe retinopathy, gastroparesis, or severe neuropathy which prevent subject's normal independent daily activities.

Where this trial is running

Boston, Massachusetts

• Massachusetts General Hospital — Boston, Massachusetts, United States (Recruiting)

Study contacts

• Principal investigator: Tatsuo Kawai — Massachusetts General Hospital
• Study coordinator: Tatsuo Kawai

Conditions Kidney Failure; Kidney Transplant; Complications; Chimera; Tolerance; Transplant