Inducing immunological tolerance in kidney transplant patients using stem cell infusion

A Single-armed, Unblinded, Non-randomized Feasibility Study of Hematopoietic Stem Cell Infusion Following a Conditioning Regimen of Total Lymphoid Irradiation (TLI) and Anti-thymocyte Globulin (ATG) in Patients With a Pre-existing, Well-functioning HLA-matched Kidney Transplant

This study is testing whether giving stem cells from the same donor to kidney transplant patients can help them stop taking their immunosuppressive medications safely.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: University of California, Los Angeles (Academic / other)
• Drugs / interventions: pembrolizumab, nivolumab, ipilimumab, rituximab, chemotherapy, immunotherapy, radiation
• Locations: 1 site (Los Angeles, California)
• Trial ID: NCT05525507 on ClinicalTrials.gov

What this trial studies

This study aims to explore the possibility of withdrawing immunosuppressive medications in patients with well-functioning kidney transplants from HLA-identical living donors by infusing hematopoietic stem cells (HPSC) from the same donor. Participants will undergo a conditioning regimen involving total lymphoid irradiation and rabbit anti-thymocyte globulin before receiving the HPSC infusion. The goal is to achieve immunological tolerance, allowing patients to live without lifelong immunosuppression. This approach builds on previous successes in simultaneous kidney and HPSC transplants, extending the concept to patients with existing transplants.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older with a well-functioning kidney transplant from an HLA-identical living donor, stable renal function, and no history of rejection.

Not a fit: Patients with a history of rejection, major post-transplant complications, or those who do not meet the eligibility criteria will not benefit from this study.

Why it matters

Potential benefit: If successful, this could allow kidney transplant patients to live without the need for lifelong immunosuppressive therapy.

How similar studies have performed: While similar approaches have shown success in simultaneous transplants, this specific method of retroactive tolerance induction in existing kidney transplants is novel and has not been previously tested.

Eligibility criteria

Recipient Inclusion Criteria:

1. Males and females ages 18 years and older with a pre- existing kidney transplant from an HLA-matched living donor.
2. Pre-existing living kidney transplant must be within 3 months to 5 years from date of scheduled HPSC infusion.
3. No history of rejection with current HLA matched kidney transplant.
4. Recipient is without post-transplant major complications, including de novo malignancy, active infection or rejection.
5. Stable renal function determined per investigator discretion.
6. Agreement to participate in the study and ability to give informed consent.
7. Meets institutional criteria for HSPC infusion.
8. 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.
9. No known contraindication to administration of rATG or radiation.
10. If participant is a female of reproductive potential (i.e., no documented absence of ovaries or uterus, history of tubal ligation, or post-menopausal status) participant must be confirmed not pregnant by a serum or urine pregnancy test) and must agree to practice a reliable form of contraception including hormonal treatments, barrier methods or intrauterine device for at least 12 months post-transplant.
11. Karnofsky Performance Score (KPS) ≥ 70.
12. Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 40% by MUGA (Multi Gated Acquisition) scan or echocardiogram.
13. Adequate liver function defined as total bilirubin ≤ 1.5 times the upper limit of normal and AST/ALT ≤ 2.0 times the upper limit of normal.
14. Adequate social support based on evaluation by the UCLA bone marrow and/or renal transplant team.

Recipient Exclusion Criteria:

1. Donor is identical twin.
2. Major ABO incompatibility with donor
3. Positive HLA Donor-Specific Antibody (DSA)
4. History of multi-organ transplantation
5. History of rejection with current HLA-matched kidney transplant
6. Known allergy to rabbit proteins
7. History of post-transplant major complications, including de novo malignancy, active/chronic infection or rejection, with the exception of low risk, early-stage malignancy with

   ≥90% 5-year survival not receiving chemotherapy or immunotherapy and non-melanomatous skin cancer.
8. History of active malignancy within the past 5 years with the exception:

   1. Low risk cancer on active surveillance
   2. Malignancy treated with curative intent with no known active disease \>2 years before the first dose of study treatment and of low potential risk for recurrence
   3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   4. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, and DCIS)
9. Worsening renal functioning over preceding 3-month interval determined per investigator discretion.
10. Pregnant (confirmed by urine or serum pregnancy test) or lactating.
11. Leukopenia (with a white blood cell count \< 3,000/µL) or thrombocytopenia (with a platelet count \< 70,000/µL).
12. EBV, CMV and BK PCR negative at time of HPSC infusion is preferred, but if they have had a history of + CMV/BK PCR, it should be resolved by 3 months.
13. Active bacterial, fungal, mycobacterial, or viral infection (including active hepatitis B and/or C).
14. Seropositivity for HIV 1 or 2 by 4th generation serum antibody/antigen testing, or HTLV I or II by serum antibody testing.
15. Renal disease with high risk of recurrence (i.e., focal segmental glomerulosclerosis).
16. Advanced hepatic fibrosis or cirrhosis secondary to hepatitis B and/or C diagnosis.
17. Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia; active extra-renal autoimmune disease requiring immunosuppression.
18. Active extra-renal autoimmune disease requiring immunosuppression.
19. Neuropsychiatric illness that precludes the ability to give informed consent and/or places the participant as high risk for non-compliance with the safety monitoring requirements of the study.
20. May not have received other immunomodulatory agents, including but not limited to tumor necrosis factor inhibitors within six months of the study treatment. Use of corticosteroids prescribed for a time-limited indication (\</= 4 weeks) and stopped at least 4 weeks before the kidney transplant is acceptable.
21. May not have received immunotherapy drugs such as immune checkpoint inhibitors (e.g. pembrolizumab, nivolumab, and ipilimumab), tumor necrosis factor inhibitors, rituximab, and interleukin-2 within six months of the study treatment.
22. Current or active abuse of alcohol and/or drugs within last 6 months.
23. Body Mass Index (BMI) ≥ 40.

Donor Inclusion Criteria:

1. HLA-matched sibling on high-resolution HLA typing who

   a. is ≥18 years of age.
2. Must meet institutional criteria for HSPC transplant donation.
3. Medically fit to tolerate peripheral blood apheresis, including weighing ≥110 pounds, hemoglobin ≥11, white blood cell count ≥ 3,000/µL, and platelets ≥ 100,000/µL.
4. Serum creatinine as expected post-kidney donation and coagulation parameter studies; or, if abnormal, the changes are not considered clinically significant.

Donor exclusion criteria:

1. Recipient is identical twin.
2. Major ABO incompatibility with recipient.
3. Medically unfit to tolerate peripheral blood apheresis (e.g. small body size, poor vascular access, not a suitable candidate for placement of a central catheter).
4. Pregnant (confirmed by urine or serum pregnancy test) or lactating.
5. Seropositivity for HIV 1 or 2 by 4th generation serum antibody/antigen testing, HTLV I or II by serum antibody testing
6. Active West Nile Virus infection.
7. Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C).
8. Psychiatric, addictive, neurological, or other disorder that compromises ability to give true informed consent for participation in this study.
9. History of active malignancy within the past 5 years with the exception:

   1. Low risk cancer on active surveillance
   2. Malignancy treated with curative intent with no known active disease \>2 years before the first dose of study treatment and of low potential risk for recurrence
   3. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   4. Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, and DCIS)
10. No use of oral anticoagulants 2 days prior to apheresis. Note: Use of aspirin and non-steroidal anti-inflammatory drugs, for pain and inflammation management purposes, are permitted to enroll in the study, but these drugs must be stopped 7 days prior to apheresis, however subjects who are taking aspirin for its anti- platelet/anti-thrombotic effect, are excluded.

Where this trial is running

Los Angeles, California

• UCLA — Los Angeles, California, United States (Recruiting)

Study contacts

• Principal investigator: Jeffrey Veale, MD — Professor of Urology
• Study coordinator: Ruth Wynne Jones

Conditions End Stage Kidney Disease; Immunological Tolerance; Kidney Transplant Failure and Rejection; Chronic Kidney Diseases; immunological tolerance; kidney transplant; tolerance; end stage kidney disease