Liver Transplantation With Tregs at MGH

NCT ID: NCT03577431

Last Updated: 2025-01-13

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 9 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2019-03-29
• Study Completion Date: 2027-04-06

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 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.

Conditions

Liver Transplant

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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.

Group Type: EXPERIMENTAL

arTreg-CSB

Intervention Type: BIOLOGICAL

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

Intervention Type: PROCEDURE

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.

cyclophosphamide

Intervention Type: DRUG

40 mg/kg administered intravenously (IV) within 24 to 72 hours prior to Treg product (arTreg-CSB) infusion.

mesna

Intervention Type: DRUG

Mesna is administered intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide. Administration of mesna is per institutional practice with cyclophosphamide.

everolimus

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: BIOLOGICAL

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.

Intervention Type: PROCEDURE

cyclophosphamide

40 mg/kg administered intravenously (IV) within 24 to 72 hours prior to Treg product (arTreg-CSB) infusion.

Intervention Type: DRUG

mesna

Mesna is administered intravenously to inhibit hemorrhagic cystitis induced by cyclophosphamide. Administration of mesna is per institutional practice with cyclophosphamide.

Intervention Type: 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.

Intervention Type: DRUG

Other Intervention Names

donor alloantigen specific regulatory T cells; CD4+CD25+CD127[lo] Treg cells; apheresis; Cytoxan®; Mesnex®; EVR; Afinitor®; Zortress®

Eligibility Criteria

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:

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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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Immune Tolerance Network (ITN)

NETWORK

Sponsor Role: collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

James F. Markmann, MD, PhD

Role: STUDY_CHAIR

University of Pennsylvania Medical Center: Transplantation

Locations

Massachusetts General Hospital: Transplantation

Boston, Massachusetts, United States

Countries

United States

Related Links

https://www.niaid.nih.gov/

National Institute of Allergy and Infectious Diseases (NIAID)

https://www.niaid.nih.gov/about/dait

Division of Allergy, Immunology, and Transplantation (DAIT)

http://www.immunetolerance.org

Immune Tolerance Network web site

Other Identifiers

DAIT ITN073ST

Identifier Type: -

Identifier Source: org_study_id