PMID- 35235342
OWN - NLM
STAT- MEDLINE
DCOM- 20220426
LR  - 20220726
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 14
IP  - 634
DP  - 2022 Mar 2
TI  - A carcinoembryonic antigen-specific cell therapy selectively targets tumor cells 
      with HLA loss of heterozygosity in vitro and in vivo.
PG  - eabm0306
LID - 10.1126/scitranslmed.abm0306 [doi]
AB  - The CEACAM5 gene product [carcinoembryonic antigen (CEA)] is an attractive target 
      for colorectal cancer because of its high expression in virtually all colorectal 
      tumors and limited expression in most healthy adult tissues. However, highly 
      active CEA-directed investigational therapeutics have been reported to be toxic, 
      causing severe colitis because CEA is expressed on normal gut epithelial cells. 
      Here, we developed a strategy to address this toxicity problem: the Tmod 
      dual-signal integrator. CEA Tmod cells use two receptors: a chimeric antigen 
      receptor (CAR) activated by CEA and a leukocyte Ig-like receptor 1 (LIR-1)-based 
      inhibitory receptor triggered by human leukocyte antigen (HLA)-A*02. CEA Tmod 
      cells exploit instances of HLA heterozygous gene loss in tumors to protect the 
      patient from on-target, off-tumor toxicity. CEA Tmod cells potently killed 
      CEA-expressing tumor cells in vitro and in vivo. But in contrast to a traditional 
      CEA-specific T cell receptor transgenic T cell, Tmod cells were highly selective 
      for tumor cells even when mixed with HLA-A*02-expressing cells. These data 
      support further development of the CEA Tmod construct as a therapeutic candidate 
      for colorectal cancer.
FAU - Sandberg, Mark L
AU  - Sandberg ML
AUID- ORCID: 0000-0002-5365-6981
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Wang, Xueyin
AU  - Wang X
AUID- ORCID: 0000-0003-1085-6366
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Martin, Aaron D
AU  - Martin AD
AUID- ORCID: 0000-0003-1012-4050
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Nampe, Daniel P
AU  - Nampe DP
AUID- ORCID: 0000-0002-4404-8220
AD  - Process Development, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, 
      CA 91301, USA.
FAU - Gabrelow, Grant B
AU  - Gabrelow GB
AUID- ORCID: 0000-0003-0803-2368
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Li, Chuck Z
AU  - Li CZ
AUID- ORCID: 0000-0001-5564-0433
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - McElvain, Michele E
AU  - McElvain ME
AUID- ORCID: 0000-0003-0661-0312
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Lee, Wen-Hua
AU  - Lee WH
AUID- ORCID: 0000-0002-6453-5464
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Shafaattalab, Sanam
AU  - Shafaattalab S
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Martire, Sara
AU  - Martire S
AUID- ORCID: 0000-0002-1570-3476
FAU - Fisher, Fernando A
AU  - Fisher FA
AUID- ORCID: 0000-0002-1118-2909
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Ando, Yuta
AU  - Ando Y
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Liu, Edwin
AU  - Liu E
AD  - Process Development, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, 
      CA 91301, USA.
FAU - Ju, David
AU  - Ju D
AUID- ORCID: 0000-0003-2000-1038
AD  - Process Development, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, 
      CA 91301, USA.
FAU - Wong, Lu Min
AU  - Wong LM
AUID- ORCID: 0000-0001-6238-7245
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Xu, Han
AU  - Xu H
AUID- ORCID: 0000-0002-1530-2162
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
FAU - Kamb, Alexander
AU  - Kamb A
AUID- ORCID: 0000-0002-8675-6620
AD  - Discovery Research, A2 Biotherapeutics, Inc., 30301 Agoura Road, Agoura Hills, CA 
      91301, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220302
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Carcinoembryonic Antigen)
RN  - 0 (HLA-A*02 antigen)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (Receptors, Chimeric Antigen)
SB  - IM
MH  - Carcinoembryonic Antigen/genetics/metabolism
MH  - Cell- and Tissue-Based Therapy
MH  - *Colorectal Neoplasms/genetics/therapy
MH  - HLA-A2 Antigen/genetics
MH  - Humans
MH  - Loss of Heterozygosity
MH  - *Receptors, Chimeric Antigen
EDAT- 2022/03/03 06:00
MHDA- 2022/04/27 06:00
CRDT- 2022/03/02 17:09
PHST- 2022/03/02 17:09 [entrez]
PHST- 2022/03/03 06:00 [pubmed]
PHST- 2022/04/27 06:00 [medline]
AID - 10.1126/scitranslmed.abm0306 [doi]
PST - ppublish
SO  - Sci Transl Med. 2022 Mar 2;14(634):eabm0306. doi: 10.1126/scitranslmed.abm0306. 
      Epub 2022 Mar 2.