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https://doi.org/10.1002/hep.31662
Title: | Immunosuppressive Drug Resistant Armored TCR T cells for immune-therapy of HCC in liver transplant patients | Authors: | MORTEZA HAFEZI Meiyin Lin Adeline Chia Alicia 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 |
Issue Date: | 29-Nov-2020 | Publisher: | Wiley | Citation: | MORTEZA HAFEZI, Meiyin Lin, Adeline Chia, Alicia 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 (2020-11-29). Immunosuppressive Drug Resistant Armored TCR T cells for immune-therapy of HCC in liver transplant patients. Hepatology. ScholarBank@NUS Repository. https://doi.org/10.1002/hep.31662 | Abstract: | Background & Aims HBV‐specific T cell receptor (HBV‐TCR) engineered T cells have the potential for treating hepatocellular carcinoma (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 minimising the associated risk of organ rejection. Approach & Results We first analysed 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 (IDRA) TCR‐T cells of desired specific (HBV or EBV) 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+) PBMCs post HBV‐TCR T cell infusions that positively correlates with clinical efficacy. In vitro experiments with TAC and MMF showed a potent inhibition of TCR‐T cell polyfunctionality. This inhibition can be effectively negated by the transient overexpression of mutated variants of CnB and IMPDH. Importantly, the resistance only lasted for 3‐5 days after which sensitivity was restored. Conclusions We engineered TCR‐T cells of desired specificities that transiently escape the immunosuppressive effects of TAC and MMF. This finding has important clinical applications for the treatment of HBV‐HCC relapses and other pathologies occurring in organ transplanted patients. | Source Title: | Hepatology | URI: | https://scholarbank.nus.edu.sg/handle/10635/189110 | ISSN: | 0270-9139 1527-3350 |
DOI: | 10.1002/hep.31662 |
Appears in Collections: | Staff Publications Elements |
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