Liver Transplantation With Tregs at UCSF

Phase 1

Terminated

Conditions: Liver Transplant

Interventions: Biological: arTreg
Procedure: leukapheresis
Drug: cyclophosphamide
Drug: mesna
Drug: everolimus

Registration Number: NCT03654040

Lead Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

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

Detailed Description: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 42

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. For candidates with a history of hepatitis C virus (HCV), completed treatment for HCV, maintaining a sustained viral response of ≥24 weeks duration by the day of transplant
5. Positive Epstein-Barr virus (EBV) antibody test, and
6. Immunizations are up-to-date based on the Advisory Committee on Immunization Practices (ACIP) recommendations for individuals with Liver Disease and Adult Vaccination, unless the investigator determines that administering a recommended immunization is not in the patient's best interest.
  
  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 before or after the 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 remain eligible:

Meets site-specific clinical donor eligibility requirements and
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
2. For cytomegalovirus (CMV) antibody negative recipients, a (CMV) antibody positive donor
3. Known contraindication to cyclophosphamide or mesna
4. Serologic evidence of human immunodeficiency virus (HIV)-1/2 infection
5. The need for chronic anti-coagulation or anti-platelet agents other than aspirin 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 condition that, in the opinion of the investigator, may interfere with study compliance
9. History of cardiac disease (ischemic heart disease requiring revascularization, history of or current treatment for dysrhythmia, or evidence of congestive heart failure), unless cleared by a cardiologist
10. Any 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.
    - This includes past, present or future enrollment in studies that affect eligibility at the time of everolimus (EVR) conversion
11. History of malignancy or any concomitant malignancy, except:
  - hepatocellular carcinoma,
  - completely treated in-situ cervical carcinoma, or
  - completely treated basal cell carcinoma.
12. Chronic use of systemic glucocorticoids or other immunosuppressives, or biologic immunomodulators.
  
  Living Donor:
There are no exclusion criteria for living donors.

Deceased Donor:

-There are no exclusion criteria for deceased donors.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
arTreg	arTreg	arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to \<90 x10\^6 total cells will be included in intent-to-treat analysis.
arTreg	leukapheresis	arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to \<90 x10\^6 total cells will be included in intent-to-treat analysis.
arTreg	cyclophosphamide	arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to \<90 x10\^6 total cells will be included in intent-to-treat analysis.
arTreg	mesna	arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to \<90 x10\^6 total cells will be included in intent-to-treat analysis.
arTreg	everolimus	arTreg: alloantigen-reactive T regulatory cells The investigational product is donor alloantigen-reactive regulatory T cells (arTreg). Supportive regimen for receipt of arTregs includes everolimus, leukapheresis, cyclophosphamide, and mesna. Note: Participants who receive at least the minimum Treg product (arTreg) dose of 30 to \<90 x10\^6 total cells will be included in intent-to-treat analysis.

Primary Outcome Measures

Name	Time	Method
Number and Severity of Adverse Events (AEs) Attributed to the Investigational Product, arTreg	From arTreg infusion through completion of study participation	* 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 \[NCI-CTCAE version 5.0, published November 27, 2017\].
Number and Severity of Adverse Events (AEs) Attributed to Supportive Regimen: Leukapheresis, Cyclophosphamide or Mesna	From ≤3 days prior to arTreg infusion through completion of study participation (Up to 3 months)	* 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 \[NCI-CTCAE version 5.0, published November 27, 2017\].
Number of Operationally Tolerant Participants	52 (± 4 weeks) after the last dose of immunosuppression	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants Who Develop a Malignancy	Time of enrollment through completion of study participation (Up to 1.8 years)	The number of participants that are diagnosed with malignancy, any type.
Incidence of ≥Grade 3 Infections Following arTreg Infusion	From arTreg infusion through completion of study participation	Grading: According to the NCI Common Terminology Criteria for Adverse Events Manual \[NCI-CTCAE version 5.0, published November 27, 2017\].
Number of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion	From arTreg infusion through completion of study participation	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.
Severity of Biopsy-Proven Acute Rejection (AR) and/or Clinical Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion	From arTreg infusion through completion of study participation	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.
Number of Chronic Rejection Events at Any Time After Alloantigen-Reactive Tregs (arTreg) Infusion	From arTreg infusion through completion of study participation	Diagnosed in accordance with Banff global assessment criteria.
Proportion of Participants Who Successfully Discontinue Tacrolimus	Post-transplant through Completion of Study Participation	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.
Duration of Operational Tolerance	Post-transplant through Completion of Study Participation	Durability of operational tolerance defined as the time from achieving the primary endpoint to immunosuppression (IS) reinitiation or to the end of trial participation.