Delayed Immunological Tolerance in Patients With Well-functioning Pre-existing HLA-matched Kidney Transplants

Inclusion criteria

• Males and females ages 18 years and older with a pre- existing kidney transplant from an HLA-matched living donor.
• Pre-existing living kidney transplant must be within 3 months to 5 years from date of scheduled HPSC infusion.
• No history of rejection with current HLA matched kidney transplant.
• Recipient is without post-transplant major complications, including de novo malignancy, active infection or rejection.
• Stable renal function determined per investigator discretion.
• Agreement to participate in the study and ability to give informed consent.
• Meets institutional criteria for HSPC infusion.
• 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.
• No known contraindication to administration of rATG or radiation.
• 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.
• Karnofsky Performance Score (KPS) ≥ 70.
• Adequate cardiac function defined as left ventricular ejection fraction (LVEF) ≥ 40% by MUGA (Multi Gated Acquisition) scan or echocardiogram.
• 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.
• Adequate social support based on evaluation by the UCLA bone marrow and/or renal transplant team.
• Recipient

Exclusion criteria

• Donor is identical twin.
• Major ABO incompatibility with donor
• Positive HLA Donor-Specific Antibody (DSA)
• History of multi-organ transplantation
• History of rejection with current HLA-matched kidney transplant
• Known allergy to rabbit proteins
• 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.
• History of active malignancy within the past 5 years with the exception:
• Low risk cancer on active surveillance
• 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
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, and DCIS)
• Worsening renal functioning over preceding 3-month interval determined per investigator discretion.
• Pregnant (confirmed by urine or serum pregnancy test) or lactating.
• Leukopenia (with a white blood cell count \< 3,000/µL) or thrombocytopenia (with a platelet count \< 70,000/µL).
• 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.
• Active bacterial, fungal, mycobacterial, or viral infection (including active hepatitis B and/or C).
• Seropositivity for HIV 1 or 2 by 4th generation serum antibody/antigen testing, or HTLV I or II by serum antibody testing.
• Renal disease with high risk of recurrence (i.e., focal segmental glomerulosclerosis).
• Advanced hepatic fibrosis or cirrhosis secondary to hepatitis B and/or C diagnosis.
• 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.
• Active extra-renal autoimmune disease requiring immunosuppression.
• 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.
• 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.
• 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.
• Current or active abuse of alcohol and/or drugs within last 6 months.
• Body Mass Index (BMI) ≥ 40.
• Donor Inclusion Criteria:
• HLA-matched sibling on high-resolution HLA typing who
• a. is ≥18 years of age.
• Must meet institutional criteria for HSPC transplant donation.
• 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.
• Serum creatinine as expected post-kidney donation and coagulation parameter studies; or, if abnormal, the changes are not considered clinically significant.
• Donor exclusion criteria:
• Recipient is identical twin.
• Major ABO incompatibility with recipient.
• 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).
• Pregnant (confirmed by urine or serum pregnancy test) or lactating.
• Seropositivity for HIV 1 or 2 by 4th generation serum antibody/antigen testing, HTLV I or II by serum antibody testing
• Active West Nile Virus infection.
• Active bacterial, fungal, mycobacterial or viral infection (including active hepatitis B and/or C).
• Psychiatric, addictive, neurological, or other disorder that compromises ability to give true informed consent for participation in this study.
• History of active malignancy within the past 5 years with the exception:
• Low risk cancer on active surveillance
• 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
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
• Adequately treated carcinoma in situ without evidence of disease (e.g., cervical cancer in situ, and DCIS)
• 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.