Donor-Alloantigen-Reactive Regulatory T Cell (darTregs) in Liver Transplantation

Exclusion Criteria

• •* 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
• •* 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).
• •* 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
• •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.