PMID- 30561769
OWN - NLM
STAT- MEDLINE
DCOM- 20200615
LR  - 20200615
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Print)
IS  - 0270-9139 (Linking)
VI  - 69
IP  - 5
DP  - 2019 May
TI  - Tuning T-Cell Receptor Affinity to Optimize Clinical Risk-Benefit When Targeting 
      Alpha-Fetoprotein-Positive Liver Cancer.
PG  - 2061-2075
LID - 10.1002/hep.30477 [doi]
AB  - Patients with hepatocellular carcinoma (HCC) have a poor prognosis and limited 
      therapeutic options. Alpha-fetoprotein (AFP) is often expressed at high levels in 
      HCC and is an established clinical biomarker of the disease. Expression of AFP in 
      nonmalignant liver can occur, particularly in a subset of progenitor cells and 
      during chronic inflammation, at levels typically lower than in HCC. This 
      cancer-specific overexpression indicates that AFP may be a promising target for 
      immunotherapy. We verified expression of AFP in normal and diseased tissue and 
      generated an affinity-optimized T-cell receptor (TCR) with specificity to 
      AFP/HLA-A*02(+) tumors. Expression of AFP was investigated using database 
      searches, by qPCR, and by immunohistochemistry (IHC) analysis of a panel of human 
      tissue samples, including normal, diseased, and malignant liver. Using in vitro 
      mutagenesis and screening, we generated a TCR that recognizes the 
      HLA-A*02-restricted AFP(158-166) peptide, FMNKFIYEI, with an optimum balance of 
      potency and specificity. These properties were confirmed by an extension of the 
      alanine scan (X-scan) and testing TCR-transduced T cells against normal and tumor 
      cells covering a variety of tissues, cell types, and human leukocyte antigen 
      (HLA) alleles. Conclusion: We have used a combination of physicochemical, in 
      silico, and cell biology methods for optimizing a TCR for improved affinity and 
      function, with properties that are expected to allow TCR-transduced T cells to 
      differentiate between antigen levels on nonmalignant and cancer cells. T cells 
      transduced with this TCR constitute the basis for a trial of HCC adoptive T-cell 
      immunotherapy.
CI  - (c) 2018 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of 
      American Association for the Study of Liver Diseases.
FAU - Docta, Roslin Y
AU  - Docta RY
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Ferronha, Tiago
AU  - Ferronha T
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Sanderson, Joseph P
AU  - Sanderson JP
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Weissensteiner, Thomas
AU  - Weissensteiner T
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Pope, George R
AU  - Pope GR
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Bennett, Alan D
AU  - Bennett AD
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Pumphrey, Nicholas J
AU  - Pumphrey NJ
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Ferjentsik, Zoltan
AU  - Ferjentsik Z
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Quinn, Laura L
AU  - Quinn LL
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Wiedermann, Guy E
AU  - Wiedermann GE
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Anderson, Victoria E
AU  - Anderson VE
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Saini, Manoj
AU  - Saini M
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Maroto, Miguel
AU  - Maroto M
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Norry, Elliot
AU  - Norry E
AD  - Adaptimmune, Abingdon, United Kingdom.
FAU - Gerry, Andrew B
AU  - Gerry AB
AD  - Adaptimmune, Abingdon, United Kingdom.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Validation Study
DEP - 20190214
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  - Carcinoma, Hepatocellular/*immunology/metabolism/therapy
MH  - HLA-A2 Antigen/*metabolism
MH  - Hep G2 Cells
MH  - Humans
MH  - Immunotherapy/methods
MH  - Liver Neoplasms/*immunology/metabolism/therapy
MH  - Receptors, Antigen, T-Cell/immunology/*therapeutic use
MH  - alpha-Fetoproteins/*metabolism
PMC - PMC6593660
EDAT- 2018/12/19 06:00
MHDA- 2020/06/17 06:00
PMCR- 2019/06/26
CRDT- 2018/12/19 06:00
PHST- 2018/06/07 00:00 [received]
PHST- 2018/12/13 00:00 [accepted]
PHST- 2018/12/19 06:00 [pubmed]
PHST- 2020/06/17 06:00 [medline]
PHST- 2018/12/19 06:00 [entrez]
PHST- 2019/06/26 00:00 [pmc-release]
AID - HEP30477 [pii]
AID - 10.1002/hep.30477 [doi]
PST - ppublish
SO  - Hepatology. 2019 May;69(5):2061-2075. doi: 10.1002/hep.30477. Epub 2019 Feb 14.