This is a single-center, prospective, open-label, non-randomized clinical trial exploring cellular therapy to facilitate immunosuppression withdrawal in liver transplant recipients.
The researchers in this study plan to enroll 9 participants. Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 to 500 x 10\^6 total cells. Participants who successfully withdraw from all immunosuppression (IS) will undergo a research biopsy at 52 weeks following IS discontinuation to determine whether they meet the primary efficacy outcome of operational tolerance. Participants determined to be operationally tolerant will be followed until 104 weeks following IS discontinuation. Participants who fail drug withdrawal after 52 weeks but before 104 weeks will be followed until week 104 or 12 weeks after resuming immunosuppression, whichever is longer. Participants who do not successfully withdraw from all IS will complete 104 weeks of High Intensity Safety Follow-up after failing immunosuppression withdrawal. \*\*\* IMPORTANT NOTICE: \*\*\* The National Institute of Allergy and Infectious Diseases and the Immune Tolerance Network do not recommend the discontinuation of immunosuppressive therapy for recipients of cell, organ, or tissue transplants outside of physician-directed, controlled clinical studies. Discontinuation of prescribed immunosuppressive therapy can result in serious health consequences and should only be performed in certain rare circumstances, upon the recommendation and with the guidance of your health care provider.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
42
Eligible participants will receive a single dose of Treg product (arTreg). The target dose is at least 90 x 10\^6 total cells. Method of receipt: peripheral intravenous (IV) infusion, administered over 20 to 30 minutes.
Leukapheresis will be the method employed to recover peripheral blood mononuclear cells (PBMCs) from the allograft recipient. The recipient will undergo the procedure prior to initiating the cyclophosphamide conditioning regimen. Procedure on Day -3 (-1 day) prior to Treg product (arTreg) IV infusion.
40 mg/kg administered intravenously (IV) following leukapheresis and between 1 to 3 days prior to Treg product (arTreg) infusion, per institutional standard of care.
University of California, San Francisco
San Francisco, California, United States
Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg
* AEs will be attributed to alloantigen-reactive Tregs (arTreg) when the AE is reported with possible or related attribution to arTreg. * Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].
Time frame: From arTreg infusion through completion of study participation
Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna
* AEs will be attributed to the supportive regimen for this study when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna. * Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].
Time frame: From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months)
Number of Operationally Tolerant Participants
Operational tolerance is defined as: * Discontinuation of all immunosuppression (IS) for 52 weeks, * Alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) ≤ 50 U/L for ≥ 2 measurements separated by ≥1 week in the 6 weeks prior to the liver biopsy at 52 weeks after the last IS dose, and * Liver biopsy at 52 weeks (±4 weeks) after the last IS dose that meets the biopsy criteria for operational tolerance, as assessed by central pathology.
Time frame: 52 (± 4 weeks) after the last dose of immunosuppression
Number of Participants Who Develop a Malignancy
The number of participants that are diagnosed with malignancy, any type.
Time frame: Time of enrollment through completion of study participation (Up to 1.8 years)
Incidence of ≥Grade 3 Infections Following arTreg Infusion
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Mesna is administered: * Intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide, and * In conjunction with the cyclophosphamide, per institutional practice with CTX.
EVR is approved for prophylaxis of allograft rejection in adults receiving a liver transplant. Per protocol: Post transplantation, subject will initially receive standard IS with tacrolimus (TAC),plus a mycophenolate product and/or steroids.Subsequently, evaluation for eligibility to be converted to EVR-based IS regimen will occur and, when applicable, proceed. Once the optimal EVR trough level is achieved,TAC dose will be reduced. When target EVR and TAC levels are maintained over two consecutive measurements, ALT liver function test (LFT) is ≤50 U/L, GGT LFT is ≤ the upper limit of normal or ≤ 1.5 times the baseline GGT, subject will be considered successfully converted to EVR-based IS regimen. EVR doses will be administered/monitored/adjusted over time.
Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].
Time frame: From arTreg infusion through completion of study participation
Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
Definitions: * AR: Diagnosed in accordance with Banff global assessment criteria * Clinical Rejection: Participants who are treated empirically based on investigator clinical suspicion in cases where a biopsy is indeterminate or in rare cases, where a biopsy cannot be performed.
Time frame: From arTreg infusion through completion of study participation
Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
Intensity of AR and/or clinical rejection events will be graded. Definitions: * AR: Diagnosed in accordance with Banff global assessment criteria * Clinical Rejection: Participants who are treated empirically based on investigator clinical suspicion in cases where a biopsy is indeterminate or in rare cases, where a biopsy cannot be performed.
Time frame: From arTreg infusion through completion of study participation
Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion
Diagnosed in accordance with Banff global assessment criteria.
Time frame: From arTreg infusion through completion of study participation
Proportion of Participants Who Successfully Discontinue Tacrolimus
Proportion of participants who, per protocol: * fulfill eligibility for tacrolimus withdrawal, * subsequently achieve their last dose of tacrolimus, * remain tacrolimus-free for ≥12 weeks, * their liver function tests, ALT and GGT, are ≤50 U/L, * and their liver biopsy performed between 12 to 26 weeks status post the last dose of tacrolimus fulfills biopsy findings\* for minimization of immunosuppression. * Biopsy findings: Liver histology will be assessed by central pathology. Biopsy findings for minimization of immunosuppression, per protocol. Reference: Demetris AJ, Bellamy C, Hubscher SG, et al. 2016 Comprehensive Update of the Banff Working Group on Liver Allograft Pathology: Introduction of Antibody-Mediated Rejection. Am J Transplant 2016.
Time frame: Post-transplant through Completion of Study Participation
Duration of Operational Tolerance
Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation.
Time frame: Post-transplant through Completion of Study Participation