PMID- 29443377
OWN - NLM
STAT- MEDLINE
DCOM- 20190131
LR  - 20211012
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 68
IP  - 2
DP  - 2018 Aug
TI  - Identification of alpha-fetoprotein-specific T-cell receptors for hepatocellular 
      carcinoma immunotherapy.
PG  - 574-589
LID - 10.1002/hep.29844 [doi]
AB  - Hepatocellular carcinoma (HCC) is the major form of liver cancer for which there 
      is no effective therapy. Genetic modification with T-cell receptors (TCRs) 
      specific for HCC-associated antigens, such as alpha-fetoprotein (AFP), can 
      potentially redirect human T cells to specifically recognize and kill HCC tumor 
      cells to achieve antitumor effects. In this study, using lentivector and peptide 
      immunization, we identified a population of cluster of differentiation 8 (CD8) T 
      cells in human leukocyte antigen (HLA)-A2 transgenic AAD mice that recognized 
      AFP(158) epitope on human HCC cells. Adoptive transfer of the AFP(158) -specific 
      mouse CD8 T cells eradicated HepG2 tumor xenografts as large as 2 cm in diameter 
      in immunocompromised nonobese diabetic severe combined immunodeficient gamma 
      knockout (NSG) mice. We then established T-cell hybridoma clones from the 
      AFP(158) -specific mouse CD8 T cells and identified three sets of paired TCR 
      genes out of five hybridomas. Expression of the murine TCR genes redirected 
      primary human T cells to bind HLA-A2/AFP(158) tetramer. TCR gene-engineered human 
      T (TCR-T) cells also specifically recognized HLA-A2(+) AFP(+) HepG2 HCC tumor 
      cells and produced effector cytokines. Importantly, the TCR-T cells could 
      specifically kill HLA-A2(+) AFP(+) HepG2 tumor cells without significant toxicity 
      to normal primary hepatocytes in vitro. Adoptive transfer of the AFP-specific 
      TCR-T cells could eradicate HepG2 tumors in NSG mice. CONCLUSION: We have 
      identified AFP-specific murine TCR genes that can redirect human T cells to 
      specifically recognize and kill HCC tumor cells, and those AFP(158) -specific 
      TCRs have a great potential to engineer a patient's autologous T cells to treat 
      HCC tumors. (Hepatology 2018).
CI  - (c) 2018 by the American Association for the Study of Liver Diseases.
FAU - Zhu, Wei
AU  - Zhu W
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Peng, Yibing
AU  - Peng Y
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Wang, Lan
AU  - Wang L
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Hong, Yuan
AU  - Hong Y
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Jiang, Xiaotao
AU  - Jiang X
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Li, Qi
AU  - Li Q
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Liu, Heping
AU  - Liu H
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Huang, Lei
AU  - Huang L
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Wu, Juan
AU  - Wu J
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Celis, Esteban
AU  - Celis E
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Merchen, Todd
AU  - Merchen T
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
AD  - Department of Surgery, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - Kruse, Edward
AU  - Kruse E
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
AD  - Department of Surgery, Medical College of Georgia, Augusta University, Augusta, 
      GA.
FAU - He, Yukai
AU  - He Y
AD  - Georgia Cancer Center, Medical College of Georgia, Augusta University, Augusta, 
      GA.
AD  - Department of Medicine, Medical College of Georgia, Augusta University, Augusta, 
      GA.
LA  - eng
GR  - R01 CA168912/CA/NCI NIH HHS/United States
GR  - R01 CA235159/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180612
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (alpha-Fetoproteins)
SB  - IM
MH  - Animals
MH  - CD8-Positive T-Lymphocytes/*immunology/metabolism
MH  - Carcinoma, Hepatocellular/*immunology
MH  - Cell Line, Tumor
MH  - Enzyme-Linked Immunosorbent Assay
MH  - Female
MH  - HLA-A2 Antigen/immunology
MH  - Hep G2 Cells
MH  - Humans
MH  - Immunotherapy/*methods
MH  - Liver Neoplasms/*immunology
MH  - Mice
MH  - Mice, Transgenic
MH  - Receptors, Antigen, T-Cell/immunology
MH  - alpha-Fetoproteins/*immunology
PMC - PMC7368991
MID - NIHMS1607925
COIS- Potential conflict of interest: Nothing to report.
EDAT- 2018/02/15 06:00
MHDA- 2019/02/01 06:00
PMCR- 2020/07/19
CRDT- 2018/02/15 06:00
PHST- 2017/09/12 00:00 [received]
PHST- 2018/01/04 00:00 [revised]
PHST- 2018/02/12 00:00 [accepted]
PHST- 2018/02/15 06:00 [pubmed]
PHST- 2019/02/01 06:00 [medline]
PHST- 2018/02/15 06:00 [entrez]
PHST- 2020/07/19 00:00 [pmc-release]
AID - 10.1002/hep.29844 [doi]
PST - ppublish
SO  - Hepatology. 2018 Aug;68(2):574-589. doi: 10.1002/hep.29844. Epub 2018 Jun 12.