DCreg in Living Donor Liver Transplantation

Study Overview
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Brief Summary
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Phase I/II, single center, prospective, open-label, non-controlled, non-randomized, interventional, cohort study in which low risk living donor liver transplant (LDLT) recipients will receive a single infusion of donor-derived DCreg 1 week prior to transplantation. All patients will be maintained on MPA and Tacrolimus (Tac) for the 1st 6 months after transplantation. At that time point, recipients meeting specific criteria will be slowly weaned off MPA per standard of care over a period of 6 months. Participants will then be evaluated for TAC weaning at 1 yr after transplantation. Those who meet specific criteria be weaned off Tac over 6 months . Successfully weaned participants who remain rejection-free will undergo 3 years of follow-up after the last dose of immunosuppression.

Detailed Description
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Phase I/II, single center, prospective, open-label, non-controlled, non-randomized, interventional, cohort study in which low risk living donor liver transplant (LDLT) recipients will receive a single infusion of donor-derived DCreg with concurrent mycophenolic acid (MPA) therapy (1/2 dose) 1 week prior to transplantation. All patients will be maintained on MPA and Tacrolimus (Tac) for the 1st 6 months after transplantation. At that time point, recipients meeting specific criteria (no rejection and permissive liver function tests (LFTs)) will be slowly weaned off MPA per standard of care over a period of 6 months. Participants will then be evaluated for TAC weaning at 1 yr after transplantation. Those who meet the criteria of no rejection and permissive LFTs will undergo a protocol liver biopsy and proceed to Tac weaning over 6 months if liver biopsy is permissive. Successfully weaned participants who remain rejection-free will undergo 3 years of follow-up after the last dose of immunosuppression. They will undergo a liver biopsy at 1 yr and 3 yrs after immunosuppression withdrawal. Participants who are removed from the study protocol at any time will return to standard of care but will continue to be followed by the study team and may undergo a liver biopsy at the end of the study (4.5 yrs after transplantation). For subjects who return to standard of care (on immunosuppression at end of study), the year 4.5 biopsy will be optional.

Official Title
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Safety and Preliminary Efficacy of Donor-derived Regulatory Dendritic Cell (DCreg) Infusion and Immunosuppression Withdrawal in Living Donor Liver Transplantation

Conditions
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Living Donor Liver Transplantation

Intervention / Treatment
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* Biological: Regulatory Donor-Derived Dendritic Cell infusion


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Donors Able to understand and provide informed consent; Male or female between the ages of 18-55; Meet all standard institutional and UNOS criteria for liver donation; For females of childbearing potential, a negative urine or serum pregnancy test; Negative for HIV (5th generation Test and NAT), HTLV-1, HTLV-2;(*) Negative for hepatitis C (antibody and NAT), hepatitis B (surface antigen and NAT)(*) Recipients Low risk recipient approved for LDLT, irrespective of gender, race, or ethnic background. Low risk is defined by absence of exclusion criteria (below). Between ages 18 and 65 years Undergoing de novo (first) liver transplant Female subjects of childbearing potential must have a negative pregnancy test upon study entry. Agreement to use contraception; according to the FDA Office of Women's Health (http://www.fda.gov/birthcontrol), there are a number of birth control methods that are more than 80% effective. Female participants of child-bearing potential must consult with their physician and determine the most suitable method(s) from this list to be used from the time that study treatment begins until 1 year after completion of immunosuppression withdrawal. (*)does not preclude donors from undergoing leukapheresis but cells may not be infused into recipient.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Biological: Regulatory Donor-Derived Dendritic Cell infusion|Regulatory dendritic cells that were prepared from a donor leukapheresis will be infused into liver transplant recipients 7 days prior to surgery|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Safety Events | 1. Safety: Safety will be determined by assessing the proportion of subjects experiencing the following events: i) CTCAE Grade 4 or higher infusion reaction; ii) CTCAE Grade 4 or higher infection; iii) Malignancy other than non-melanoma skin cancer or HCC recurrence; iv) Rejection resulting in recipient death or retransplantation; v) Biopsy-proven severe acute rejection; vi) Any grade chronic rejection; vii) Non-surgical graft loss; viii) Recipient death; | 6 years | 
| Preliminary Efficacy | Proportion of patients able to achieve staged immunosuppression withdrawal with operational tolerance | 2.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Donor Specific Antigen (DSA) levels | DSA levels early (<6 weeks) and late (> 6 weeks) after transplantation | 6 years | 
| Change in renal function | Change in renal function | 1 year post-transplantation (prior to weaning) 4.5 years post transplantation | 
| Change in Quality of Life | Change in Quality of Life as measured by the Short Form 36 (SF-36) Quality of Life questionnaire | 1 year post-transplantation (prior to weaning) 4.5 years post transplantation | 
| Change in cardiovascular risk factors | Change in cardiovascular risk factors including incidence of hypertension necessitating medication, post-transplant diabetes, hyperlipidemia, hypercholesterolemia | 1 year post-transplantation (prior to weaning) 4.5 years post transplantation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Regulatory Dendritic Cells