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 who will receive at least the target Treg product (arTreg-CSB) dose of 2.5 x 10\^6 cells. Participants who receive at least 1 x 10\^6 cells but \< 2.5 x 10\^6 cells as a result of low cell yield will be included in intent-to-treat (ITT) analysis. Participants who successfully withdraw from all immunosuppression will undergo a research biopsy at 52 weeks following drug 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 drug discontinuation and have a research biopsy at that time to confirm that they remain operationally tolerant. 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. The research biopsy at week 104 will be optional for these participants. Participants who do not successfully withdraw from all immunosuppression 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
9
Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10\^6 total cells. If a minimum arTreg-CSB dose of 1 to \< 2.5 x 10\^6 cells, the product will be infused. If the dose obtained after product manufacture is \< 1 x 10\^6 cells, the product will not be infused. When the dose obtained after product manufacture is \> 125 x 10\^6 cells, a dose aliquot will be prepared so that the administered dose will be ≤ 125 x 10\^6 cells, and ≥ 2.5 to 125 x 10\^6 total cells. Method of receipt: peripheral intravenous (IV) infusion, administered over 15 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 72 to 120 hours prior to Treg product (arTreg-CSB) IV infusion.
Massachusetts General Hospital: Transplantation
Boston, Massachusetts, United States
Number of Adverse Events (AEs) Attributed to the Investigational Product, arTreg-CSB
The number of AEs attributed to the investigational product, arTreg-CSB. AEs will be attributed to arTreg-CSB when the AE is reported with possible or related attribution to arTreg-CSB.
Time frame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg-CSB
Assessment of the intensity of AEs attributed to the investigational product, arTreg-CSB. AEs will be attributed to arTreg-CSB when the AE is reported with possible or related attribution to arTreg-CSB. Grading according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Number of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
The number of AEs attributed to the investigational product's supportive regimen (leukapheresis, cyclophosphamide, and mesna). AEs will be attributed to the supportive regimen when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna.
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Severity of Adverse Events (AEs) Attributed to the Investigational Product's Supportive Regimen (Leukapheresis, Cyclophosphamide and Mesna)
Assessment of the intensity of AEs attributed to the investigational product's supportive regimen (e.g., leukapheresis, cyclophosphamide, and mesna). AEs will be attributed to the supportive regimen when the AE is reported with possible or related attribution to leukapheresis, cyclophosphamide, or mesna. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
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40 mg/kg administered intravenously (IV) within 24 to 72 hours prior to Treg product (arTreg-CSB) infusion.
Mesna is administered intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide. Administration of mesna is per institutional practice with cyclophosphamide.
EVR, an immunosuppressant (IS), is approved by the FDA for the prophylaxis of allograft rejection in adults receiving a liver transplant. Between day 30 and wk. 48 post-transplant, participant evaluation for eligibility to be converted to an EVR-based IS regimen will occur. At the start of conversion from tacrolimus (TAC) to EVR IS:EVR will be started at 1.5 mg taken by mouth BID, with dose adjusted to achieve a trough blood level of 5-8 ng/mL. Once an EVR trough level of ≥ 5 ng/mL is achieved, baseline TAC dose will be reduced to achieve a trough level of 3-5 ng/mL. When target EVR and TAC levels are achieved/ maintained over two consecutive measurements, and liver function tests, ALT and GGT, are ≤50 U/L, participants will be considered successfully converted to EVR-based IS regimen. EVR doses will be administered, monitored and adjusted over time, per protocol.
Number of Operationally Tolerant Participants
Operational tolerance is defined as: * Discontinuation of immunosuppression for 52 weeks, * Alanine aminotransferase (ALT) ≤ 50 U/L, and * A liver biopsy at 52 weeks (±4 weeks) after the last dose of immunosuppression that meets the criteria noted per protocol. * Liver histology will be assessed by central pathology.
Time frame: 52 weeks (±4 weeks) after the last dose of immunosuppression
Number of Adverse Events (AEs) Attributed to Leukapheresis
Number of AEs with possible or related attribution to leukapheresis.
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Severity of Adverse Events (AEs) Attributed to Leukapheresis
Assessment of the intensity of AEs with possible or related attribution to leukapheresis. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Number of Adverse Events (AEs) Attributed to Cyclophosphamide
Number of AEs with possible or related attribution to cyclophosphamide.
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Severity of Adverse Events (AEs) Attributed to Cyclophosphamide
Assessment of the intensity of AEs with possible or related attribution to cyclophosphamide. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Number of Adverse Events (AEs) Attributed to Mesna
Number of AEs with possible or related attribution to mesna.
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Severity of Adverse Events (AEs) Attributed to Mesna
Assessment of the intensity of AEs with possible or related attribution to mesna. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From ≤3 days prior to arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Number of Participants Who Experience ≥Grade 3 Infections Following arTreg-CSB Infusion
Number of participants that experience ≥grade 3 infectious AEs status post arTreg-CSB infusion. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Number of Biopsy-Proven Acute or Chronic Rejections
Number of participants with biopsy-proven AR or CR. The diagnosis of biopsy-proven acute and chronic allograft rejection will be diagnosed in accordance with Banff global assessment criteria.
Time frame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Severity of Biopsy-Proven Acute Rejections
Assessment of the intensity of biopsy-proven AR at any time status post participant's receipt of arTreg-CSB infusion. Intensity of AR will be graded in accordance with the Banff global assessment criteria. Reference: Banff schema for grading liver allograft rejection: an international consensus document. Hepatology 1997;25:658-63.
Time frame: From arTreg-CSB infusion through completion of study participation (Up to 4.5 years)
Proportion of Participants with a Composite Outcome Measure of CR, Steroid Refractory AR, Retransplantation or Death Following Everolimus Conversion
The proportion of participants who develop ≥1 of the following events following initiation of everolimus conversion: refractory Acute Rejection (AR), Chronic Rejection (CR), undergo retransplantation, or die during study participation. Everolimus is FDA approved for use in liver and kidney transplantation for prophylaxis of organ rejection.
Time frame: From ≥30 days post-transplant through completion of study participation (Up to 4.5 years)
Number of AEs Attributed to Immunosuppression Withdrawal
Number of AEs possibly or definitely related to immunosuppression withdrawal.
Time frame: From ≥30 days post-transplant through completion of study participation (Up to 4.5 years)
Severity of AEs Attributed to Immunosuppression Withdrawal
Assessment of the intensity of AEs possibly or definitely related to immunosuppression withdrawal. Assessment of the intensity of AEs will be graded according to the NCI Common Terminology Criteria for Adverse Events \[NCI-CTCAE version 4.03\].
Time frame: From ≥30 days post-transplant through completion of study participation (Up to 4.5 years)
Number of Participants who Develop a Malignancy
The number of participants that are diagnosed with malignancy, any type.
Time frame: Day of transplant through completion of study participation (Up to 4.5 years)
Number of Participants who Develop de novo Donor Specific Antibodies (DSA)
A de novo donor-specific alloantibody (DSA) is a newly developed alloantibody that targets the donor organ. Alloantibodies are important mediators of acute and chronic rejection. This measure is calculated as time from transplant until the earliest time of development of any de novo DSA.
Time frame: Baseline (pre liver transplant) through completion of study participation (Up to 4.5 years)
Number of Participants who Develop de novo non-DSA HLA Antibodies
The number of participants who, following liver transplant, develop anti-donor HLA alloantibodies defined by the presence of anti-HLA IgG antibodies.
Time frame: Baseline (pre liver transplant) through Completion of Study Participation (Up to 4.5 years)
Proportion of Participants who, Though Clinically Stable for 52 Weeks after Discontinued Immunosuppression per Protocol Schedule, do not Fulfill the Study Definition of Tolerance
Proportion of participants who have discontinued immunosuppression for 52 weeks, but have: * either an ALT greater than 50 U/L or * a liver biopsy at 52 weeks that does not show rejection but does not meet the biopsy criteria for operational tolerance (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 (Up to 4.5 years)
Duration of Operational Tolerance
Defined as the time from achievement of the primary endpoint to immunosuppression reinitiation or to the end of trial participation. Inclusion in this analysis is limited to those participants classified as operationally tolerant for the primary outcome measure.
Time frame: Post-transplant through Completion of Study Participation (Up to 4.5 years)
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 test, ALT is ≤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 (Up to 4.5 years)