Immunosuppressive Drug‐Resistant Armored T‐Cell Receptor T Cells for Immune Therapy of HCC in Liver Transplant Patients

作者：Morteza Hafezi, Meiyin Lin, Adeline Chia, Alicia S. Chua, Zi Zong Ho, Royce Fam, Damien Tan, Joey Aw, Andrea Pavesi, Thinesh Lee Krishnamoorthy, Wan Cheng Chow, Wenjie Chen, Qi Zhang, Lu‐En Wai, Sarene Koh, Anthony T. Tan, Antonio Bertoletti · 发表于：Hepatology · 年份：2020 · DOI：10.1002/hep.31662 · 被引用次数：58 · 研究领域：CAR-T cell therapy research、Hepatitis B Virus Studies、Immune Cell Function and Interaction

Background and Aims HBV‐specific T‐cell receptor (HBV‐TCR) engineered T cells have the potential for treating HCC relapses after liver transplantation, but their efficacy can be hampered by the concomitant immunosuppressive treatment required to prevent graft rejection. Our aim is to molecularly engineer TCR‐T cells that could retain their polyfunctionality in such patients while minimizing the associated risk of organ rejection. Approach and Results We first analyzed how immunosuppressive drugs can interfere with the in vivo function of TCR‐T cells in liver transplanted patients with HBV‐HCC recurrence receiving HBV‐TCR T cells and in vitro in the presence of clinically relevant concentrations of immunosuppressive tacrolimus (TAC) and mycophenolate mofetil (MMF). Immunosuppressive Drug Resistant Armored TCR‐T cells of desired specificity (HBV or Epstein‐Barr virus) were then engineered by concomitantly electroporating mRNA encoding specific TCRs and mutated variants of calcineurin B (CnB) and inosine‐5′‐monophosphate dehydrogenase (IMPDH), and their function was assessed through intracellular cytokine staining and cytotoxicity assays in the presence of TAC and MMF. Liver transplanted HBV‐HCC patients receiving different immunosuppressant drugs exhibited varying levels of activated (CD39 + Ki67 + ) peripheral blood mononuclear cells after HBV‐TCR T‐cell infusions that positively correlate with clinical efficacy. In vitro experiments with TAC and MMF showed a potent inhibition...