PMID- 33323464
OWN - NLM
STAT- MEDLINE
DCOM- 20210920
LR  - 20210920
IS  - 2051-1426 (Electronic)
IS  - 2051-1426 (Linking)
VI  - 8
IP  - 2
DP  - 2020 Dec
TI  - In vivo therapeutic effects of affinity-improved-TCR engineered T-cells on 
      HBV-related hepatocellular carcinoma.
LID - 10.1136/jitc-2020-001748 [doi]
LID - e001748
AB  - BACKGROUND: In patients with hepatitis B virus (HBV)-related hepatocellular 
      carcinoma (HCC), virus-specific cytotoxic T lymphocytes (CTLs) fail to eliminate 
      HCC cells expressing HBV antigens. As the expression of viral antigen in 
      HBV-associated HCC may decrease to allow tumor to escape immune attacks, we 
      hypothesized that an HBV surface antigen (HBsAg)-specific 
      affinity-improved-T-cell receptor (TCR) will enable T cells to target HCC more 
      effectively than corresponding wild-type-TCR. We also postulated that TCR 
      promiscuity can be exploited to efficiently capture HBV variants that can hinder 
      CTL-based therapeutics. METHODS: We applied flexi-panning to isolate 
      affinity-improved TCRs binding to a variant antigen, the human leukocyte antigen 
      (HLA)-A*02:01-restricted nonapeptide HBs(371-379)-ILSPFLPLL, from libraries 
      constructed with a TCR cloned using the decapeptide HBs(370-379)-SIVSPFIPLL. The 
      potency and safety of the affinity-improved-TCR engineered T-cells (Ai-TCR-T) 
      were verified with potentially cross-reactive human and HBV-variant peptides, 
      tumor and normal cells, and xenograft mouse models. RESULTS: Ai-TCR-T cells 
      retained cognate HBV antigen specificity and recognized a wide range of HBV 
      genotypic variants with improved sensitivity and cytotoxicity. Cell infusions 
      produced complete elimination of HCC without recurrence in the xenograft mouse 
      models. Elevated accumulation of CD8(+) Ai-TCR-T cells in tumors correlated with 
      tumor shrinkage. CONCLUSION: The in vitro and in vivo studies demonstrated that 
      HBsAg-specific Ai-TCR-T cells had safety profiles similar to those of their 
      wild-type counterparts and significantly enhanced potency. This study presents an 
      approach to develop new therapeutic strategies for HBV-related HCC.
CI  - (c) Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No 
      commercial re-use. See rights and permissions. Published by BMJ.
FAU - Liu, Qi
AU  - Liu Q
AUID- ORCID: 0000-0001-6273-9351
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
AD  - University of the Chinese Academy of Sciences, Beijing, China.
FAU - Tian, Ye
AU  - Tian Y
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
FAU - Li, Yanyan
AU  - Li Y
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
FAU - Zhang, Wei
AU  - Zhang W
AD  - Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of 
      Biomedicine and Health, Hefei, Anhui, China.
FAU - Cai, Wenxuan
AU  - Cai W
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
FAU - Liu, Yaju
AU  - Liu Y
AD  - Hefei Institute of Stem Cell and Regenerative Medicine, Guangzhou Institutes of 
      Biomedicine and Health, Hefei, Anhui, China.
FAU - Ren, Yuefei
AU  - Ren Y
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
AD  - School of Life Sciences, University of Science and Technology of China, Hefei, 
      Anhui, China.
FAU - Liang, Zhaoduan
AU  - Liang Z
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
FAU - Zhou, Peipei
AU  - Zhou P
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
AD  - Institute of Physical Science and Information Technology, Anhui University, 
      Hefei, Anhui, China.
FAU - Zhang, Yajing
AU  - Zhang Y
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
AD  - University of the Chinese Academy of Sciences, Beijing, China.
FAU - Bao, Yifeng
AU  - Bao Y
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China.
FAU - Li, Yi
AU  - Li Y
AD  - State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine 
      and Health, Guangzhou, China li_yi@gibh.ac.cn.
AD  - University of the Chinese Academy of Sciences, Beijing, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Immunother Cancer
JT  - Journal for immunotherapy of cancer
JID - 101620585
SB  - IM
MH  - Animals
MH  - Carcinoma, Hepatocellular/immunology/pathology/*virology
MH  - Hepatitis B virus/*pathogenicity
MH  - Humans
MH  - Liver Neoplasms/pathology/*virology
MH  - Male
MH  - Mice
MH  - T-Lymphocytes/*metabolism
MH  - Tissue Engineering/*methods
MH  - Xenograft Model Antitumor Assays
PMC - PMC7745518
OTO - NOTNLM
OT  - CD8-Positive T-lymphocytes
OT  - adoptive
OT  - cell engineering
OT  - immunohistochemistry
OT  - immunotherapy
OT  - liver neoplasms
COIS- Competing interests: None declared.
EDAT- 2020/12/17 06:00
MHDA- 2021/09/21 06:00
PMCR- 2020/12/15
CRDT- 2020/12/16 05:28
PHST- 2020/11/15 00:00 [accepted]
PHST- 2020/12/16 05:28 [entrez]
PHST- 2020/12/17 06:00 [pubmed]
PHST- 2021/09/21 06:00 [medline]
PHST- 2020/12/15 00:00 [pmc-release]
AID - jitc-2020-001748 [pii]
AID - 10.1136/jitc-2020-001748 [doi]
PST - ppublish
SO  - J Immunother Cancer. 2020 Dec;8(2):e001748. doi: 10.1136/jitc-2020-001748.