Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation
Condition: Liver Transplantation
Intervention: Anti-Thymocyte Globulin - Rabbit; darTreg Infusion; Everolimus; Tacrolimus; Mycophenolate mofetil; Prednisone; Acetaminophen; Diphenhydramine; Anti-Infective Prophylaxis; Leukapheresis; Blood draws; Liver biopsies; Liver transplantation
Intervention description: Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects will be given a dose range of 3.0-4.5 mg/kg total, in divided doses of 1.5 mg/kg/day. Subjects who meet eligibility criteria for Thymoglobulin® administration will be given 1.5 mg/kg intravenously (IV) on post-operative day 3, within 72 hours of transplantation. Additional doses of 1.5 mg/kg IV will be administered until CD3 count is <50/mm^3 or when the maximal dose of 4.5/mg/kg has been given.; A single dose darTreg infusion (Cohorts 2 - 4) will be received as per protocol.; Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Subjects meeting eligibility criteria for Treg-supportive IS regimen will begin EVR no sooner than 30 days after liver transplantation and no later than 44 days after transplantation; with target trough levels of 6-8 μg/L.EVR target trough levels will be further reduced to 4-6 μg/L 24 - 26 weeks after transplantation.; Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Between 30 and 44 days following transplant: Subjects who are not eliminated by Exclusion Criteria C1 (Protocol Section 14.3.1) will proceed in the study and receive either TAC-based or EVR- based IS, based on eligibility Criteria C2 (Section 4.3.4 )
TAC-based IS: reduce TAC trough level to 3-8 μg/dL; continue MMF
EVR-based IS: reduce TAC trough level to 3-8 μg/dL; EVR target trough level of 6-8 μg/dL; decrease then discontinue MMF; Liver transplantation/Treg-supportive immunosuppression (IS) treatment. 1000 mg total daily dose. MMF will be initiated within 24 hours of transplantation. MMF must be discontinued as soon as target EVR trough levels have been achieved.; Liver transplantation/Treg-supportive immunosuppression (IS) treatment. Solumedrol 500 mg will be given IV on the day of transplantation. Additional Solumedrol will be prescribed according to site-specific standard of care. Oral prednisone should be initiated once oral medication is tolerated.; Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 650mg of acetaminophen will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.; Pre-medication for single dose darTreg infusion (Cohorts 2 - 4). 25-50mg of diphenhydramine will be administered intravenously or by mouth 30-60 minutes prior to the darTreg infusion.; Intravenous ganciclovir and/or oral Valcyte will be administered for the prophylaxis of cytomegalovirus (CMV) and Epstein-Barr Virus (EBV) for at least six months after liver transplantation.; Leukapheresis is necessary to ensure collection of adequate numbers of autologous Tregs to support ex vivo expansion of darTregs for infusion after liver transplantation.
Participants enrolled in Cohorts 3 and 4 will undergo leukapheresis. Participants enrolled in Cohort 2 will have either whole blood collection or leukapheresis for the purpose of isolating autologous Tregs for later manufacture. If a cohort 2 subject has a hemoglobin level >/=10.5 gm/dL, he or she will undergo phlebotomy. If the patient has a hemoglobin level </=10.5 gm/dL and remains eligible for the study, the patient will undergo leukapheresis.; Blood draws are necessary to carefully and frequently evaluate allograft function after liver transplantation and treatment with Treg-supportive IS as well as after darTreg infusion. Peripheral blood samples will be collected and analyzed per protocol throughout subject participation in this study.; Subjects will have a liver biopsy for this study 12-14 weeks after transplantation. For subjects receiving darTregs, a second biopsy will be performed 7-10 days after darTregs infusion.; Inclusion in this trial is in the setting of subjects defined as having end-stage liver disease and listed for primary solitary liver transplant.
Intervention MeSH terms: Acetaminophen; Diphenhydramine; Promethazine; Mycophenolic Acid; Valganciclovir; Ganciclovir; Anti-Infective Agents; Prednisone; Methylprednisolone Hemisuccinate; Everolimus; Liver Extracts; Tacrolimus; Thymoglobulin; Antilymphocyte Serum
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 15.0
Sex: All
Minimum age: 21 Years
Maximum age: 70 Years
Healthy volunteers: No
Keywords: Donor-Alloantigen-Reactive Regulatory T Cell Therapy; Tregs; Cell- and Tissue-Based Therapy; Immunotherapy, Adoptive; Liver Transplantation

Summary:

      The purpose of this study is look at the safety of:

        -  Taking a specific combination of immunosuppressant drugs after liver transplantation

        -  Receiving one of three different doses of donor-alloantigen-reactive regulatory T cells
           (darTregs) while taking this specific combination of drugs
    

Eligibility criteria:

        Inclusion Criteria:

          -  Subjects who meet all of the following criteria are eligible for enrollment as study
             participants:

               -  Able to understand and provide informed consent

               -  End-stage liver disease and listed for primary solitary liver transplant

               -  Have a calculated Model for End Stage Liver Disease (MELD) score ≤ 25 at the time
                  of study entry/consent

               -  Female and male subjects with reproductive potential must agree to use effective
                  methods of birth control for the duration of the study.

               -  If history of Hepatitis C Virus (HCV), have completed or are in current treatment
                  for HCV AND have no detectable HCV RNA.

               -  Subjects with HCC meeting Milan criteria.

        Exclusion Criteria:

          -  Below are exclusion criteria to be assessed at study enrollment, prior to Stage 1
             study procedures. Subjects who meet any of these criteria are not eligible for Stage 1
             study procedures. Note that subjects in Cohort 1a or 1b will NOT undergo leukapheresis
             regardless of eligibility.

               -  End stage liver disease secondary to autoimmune etiology (autoimmune hepatitis,
                  primary biliary cirrhosis, or primary sclerosing cholangitis)

               -  History of less than 5 years remission of malignancy, except for 1) HCC or 2)
                  history of adequately treated in-situ cervical carcinoma, or adequately treated
                  basal or squamous cell carcinoma of the skin.

               -  History of previous organ, tissue or cell transplant

               -  Serologic evidence of human immunodeficiency (HIV) 1 or -2 infection

               -  Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) sero-negativity (EBV or CMV
                  naïve candidates)

               -  Chronic use of systemic glucocorticoids or other Immunosuppression (IS), or
                  biologic immunomodulators

               -  Chronic condition requiring anti-coagulation after liver transplantation

               -  Any chronic illness or prior treatment which, in the opinion of the investigator,
                  precludes study participation

               -  Participation in any other studies that involved investigational drugs or
                  regimens in the preceding year

               -  Received any vaccination within 28 days prior to leukapheresis or blood
                  collection for Treg manufacture

               -  Hemoglobin <9.0 g/dL within 10 days prior to screening

               -  Neutrophils <1,500/μL within 10 days prior to screening

               -  Platelets <40,000/μL within 10 days prior to screening

          -  Thymoglobulin Exclusion Criteria B (Stage 2):

               -  Below are exclusion criteria to be assessed prior to administration of
                  Thymoglobulin®. Subjects who meet any of these criteria should not receive
                  Thymoglobulin®:

                    -  Calculated Model for End Stage Liver Disease (MELD) score >25 at the time of
                       deceased donor liver transplant

                    -  Last alpha-fetoprotein (AFP) obtained prior to liver transplantation >400
                       μg/L for candidates with Hepatocellular Carcinoma (HCC)

                    -  Unacceptable Peripheral Blood Mononuclear Cells (PBMC) product for
                       participants enrolled in Cohorts 2, 3, or 4 per the UCSF The Human Islet and
                       Cellular Transplant Facility (HICTF) manufacturing specifications

                    -  Absence of donor spleen for any participants

                    -  Human leukocyte antigen (HLA)-DR (DR is one of class II antigens) matched to
                       donor at both loci

                    -  Subject is < 21 or >70 years of age at the time of transplantation

                    -  Located in the intensive care unit 72 hours after transplantation

                    -  Hemoglobin <8.0 g/dL

                    -  Absolute neutrophil count <1,200/μL

                    -  Platelets <40,000/μL

                    -  Positive pregnancy test for females of child bearing potential

                    -  Unexpected histopathology on back table liver biopsy that contraindicates
                       the initiation of Treg supportive IS regimen.

                    -  Development of a condition requiring chronic anti-coagulation.

                    -  Hypersensitivity to rabbit proteins or any excipient in Thymoglobulin®.

                    -  Detectable HCV RNA or less than six months after end of treatment for HCV at
                       the time of transplantation (i.e., does not meet criteria for SVR).

               -  Below are exclusion criteria to be assessed prior to conversion to Everolimus
                  (EVR)-based IS regimen. (Assessed at day 30-44 after transplantation for
                  continuation in the trial) All subjects regardless of eligibility for EVR
                  conversion, with any of the following will not receive darTregs and will move
                  into safety follow up:

                    -  Explanted liver with evidence of increased risk of recurrent cancer risk
                       (hepatocellular (HCC) tumor burden exceeding the Milan criteria; presence of
                       vascular invasion; cholangiocarcinoma morphology)

                    -  Insufficient depletion of recipient T cells, defined as a nadir CD3 count
                       ≥50 cells μ/L (50 cells /mcL) or total lymphocyte count ≥ 0.1x 109/L if CD3
                       count is unavailable

                    -  Development of a condition requiring chronic anti-coagulation.

                    -  Clinical evidence of biliary obstruction

                    -  Alanine Aminotransferase (ALT) >2.0 x upper limit of normal (ULN)

                    -  Inability to taper off corticosteroids by 44 days (+/- 2 days) after
                       transplant

                    -  Detectable circulating HCV RNA.

        Everolimus Conversion Criteria C2 (assessed prior to conversion to EVR based IS regimen;
        EVR cannot be initiated prior to 30 days after liver transplantation). Subjects with any of
        the following will remain on TAC-based IS regimen.

          -  Evidence of hepatic artery stenosis or thrombosis by Doppler examination or
             angiography within 7 days prior to conversion

          -  Urine protein/creatinine ratio >1.0 within 7 days prior to conversion

          -  Calculated GFR less than 30 ml/min per MDRD4 (Modification of Diet in Renal Disease
             Study) equation within 7 days prior to conversion

          -  Physical examination documentation of abnormal wound healing or uncontrolled wound
             infection

          -  Hemoglobin <8.0 g/dL within 7 days prior to conversion

          -  Absolute neutrophil count <1,200/μL within 7 days prior to conversion

          -  Platelets <50,000/μL within 7 days prior to conversion

             *Below are exclusion criteria to be assessed prior to darTreg infusion for subjects in
             Cohorts 2, 3, and 4 only. Subjects in Cohort 2, 3, or 4 who meet any of these criteria
             should not receive a darTreg-infusion:

          -  Inability or unwillingness of participant to give additional written informed consent

          -  Unacceptable darTreg product

          -  Detectible circulating Epstein-Barr Virus (EBV) or cytomegalovirus (CMV) DNA within 10
             days prior to darTreg infusion

          -  Detectible Hepatitis B Virus (HBV) DNA within 10 days prior to darTreg infusion

          -  Detectable circulating HCV RNA within 10 days prior to darTreg infusion.

          -  Alanine Aminotransferase (ALT) >1.5x upper limit of normal within 10 days of darTreg
             infusion

          -  Most recent, but not greater than 10 days prior to darTreg infusion,12 hour TAC trough
             levels of > 8 μg/L for all subjects

          -  Most recent, but not greater than 10 days prior to darTreg infusion,12 hour EVR trough
             levels of < 5 μg/L for subjects on EVR

          -  For subjects on EVR-based IS, received Mycophenolate Mofetil (MMF) within 10 days
             prior to darTreg infusion

          -  Evidence of acute rejection or chronic rejection according to Banff criteria on
             protocol allograft biopsy based on local assessment

          -  Received any vaccination within 14 days prior to darTreg infusion

          -  Positive pregnancy test for females of child bearing potential

          -  Inability or unwillingness of participant to comply with study protocol or procedures.

          -  Calculated glomerular filtration rate (eGFR) less than 40 ml/min per MDRD4 equation
             within 10 days prior to infusion.