Purpose

This is a single-center, prospective, open-label, non-randomized clinical trial exploring cellular therapy to facilitate immunosuppression withdrawal in liver transplant recipients.

Condition

Eligibility

Eligible Ages
Between 18 Years and 70 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Inclusion Criteria

Eligibility: Recipient: - Individuals must meet all of the following criteria to be eligible for this study: 1. Able to understand and provide informed consent 2. End-stage liver disease and listed for a living or deceased-donor primary solitary liver transplant 3. Agreement to use contraception 4. Positive Epstein-Barr virus (EBV) antibody test and 5. In the absence of contraindication, vaccinations must be up to date per the DAIT Guidance for Patients in Transplant Trials (Refer to the Manual of Procedures) Living Donor: - Living donors must meet all of the following criteria to be eligible for this study: 1. Able to understand and provide informed consent 2. Meets site-specific clinical donor eligibility requirements 3. Meets donor eligibility manufacturing requirements within 7 days prior to blood collection for manufacturing and 4. Willingness to donate appropriate biologic samples. Deceased Donor: Deceased donors must meet the following criteria for their recipients to be eligible for this study: 1. Meets site-specific clinical donor eligibility requirements and 2. Meets donor eligibility manufacturing requirements. Note: - There are several stages to this study. - Eligibility is evaluated at many time points during the study to assess whether a participant is safe to proceed to the next study stage.

Exclusion Criteria

Recipient: - Individuals who meet any of the following criteria will not be eligible for this study: 1. History of previous organ, tissue or cell transplant requiring or potentially requiring immunosuppression 2. For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor 3. Known contraindication to cyclophosphamide or Mesna administration 4. Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection 5. The need for chronic anti-coagulation that cannot be safely discontinued for a minimum of 1 week to safely perform a liver biopsy 6. End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis, primary biliary cirrhosis, or primary sclerosing cholangitis) or other contraindications to drug withdrawal 7. Psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up visit schedule 8. Any form of substance abuse, psychiatric disorder, or other condition that, in the opinion of the investigator, may interfere with study compliance 9. Past or current medical problems, treatments or findings that are not listed above, which, in the opinion of the investigator, may: -- pose additional risks from participation in the study, - interfere with the candidate's ability to comply with study requirements, or - impact the quality or interpretation of the data obtained from the study. 10. History of malignancy with a risk of recurrence judged by the investigator to be >1%, except for: -- hepatocellular carcinoma, -- completely treated in-situ cervical carcinoma, or -- completely treated basal cell carcinoma. 11. Chronic use of systemic glucocorticoids or other immunosuppressives, or biologic immunomodulators. Living Donor: Living donors who meet the following criteria will not be eligible for this study: 1. Any condition that, in the opinion of the investigator, may pose additional risks from participation in the study, may: -- interfere with the participant's ability to comply with study requirements or --impact the quality or interpretation of the data obtained from the study. Deceased Donor: Recipients of livers from deceased donors who meet the following criteria are ineligible for this study: 1. Any condition that, in the opinion of the investigator, may pose additional risks or may impact the quality or interpretation of the data obtained from the study.

Study Design

Phase
Phase 1/Phase 2
Study Type
Interventional
Allocation
N/A
Intervention Model
Single Group Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
arTreg-CSB
arTreg CSB: alloantigen-reactive T regulatory cells costimulatory blockade per protocol. The investigational product is donor alloantigen-specific T regulatory cells (arTreg-CSB). Supportive regimen for receipt of arTregs-CSB includes everolimus, leukapheresis, cyclophosphamide, and mesna. Participants will receive a single dose of Treg product (arTreg-CSB). The target dose is 2.5 to 125 x 10^6 total cells. arTreg-CSB will be administered as a single peripheral intravenous (IV) infusion over approximately 15 to 30 minutes. Note: Participants who receive at least the minimum Treg product (arTreg-CSB) dose of 1 to < 2.5 x 10^6 cells will be included in intent-to-treat analysis.
  • Biological: arTreg-CSB
    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.
    Other names:
    • donor alloantigen specific regulatory T cells
    • CD4+CD25+CD127[lo] Treg cells
  • Procedure: leukapheresis
    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.
    Other names:
    • apheresis
  • Drug: cyclophosphamide
    40 mg/kg administered intravenously (IV) within 24 to 72 hours prior to Treg product (arTreg-CSB) infusion.
    Other names:
    • Cytoxan®
  • Drug: mesna
    Mesna is administered intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide. Administration of mesna is per institutional practice with cyclophosphamide.
    Other names:
    • Mesnex®
  • Drug: everolimus
    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.
    Other names:
    • EVR
    • Afinitor®
    • Zortress®

More Details

Status
Active, not recruiting
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)

Study Contact

Detailed Description

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.