Please use this identifier to cite or link to this item: 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

Show full item record
Files in This Item:
File Description SizeFormatAccess SettingsVersion 
hep.31662.pdf20.58 MBAdobe PDF

OPEN

Post-printView/Download

Google ScholarTM

Check

Altmetric


Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.