PMID- 29675462
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20201001
IS  - 2372-7705 (Print)
IS  - 2372-7705 (Electronic)
IS  - 2372-7705 (Linking)
VI  - 3
DP  - 2016
TI  - An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like 
      affinity to maintain antigen specificity.
PG  - 1-9
LID - 10.1038/mto.2016.23 [doi]
AB  - Chimeric antigen receptors (CARs) are synthetic receptors that usually redirect T 
      cells to surface antigens independent of human leukocyte antigen (HLA). Here, we 
      investigated a T cell receptor-like CAR based on an antibody that recognizes 
      HLA-A*0201 presenting a peptide epitope derived from the cancer-testis antigen 
      NY-ESO-1. We hypothesized that this CAR would efficiently redirect transduced T 
      cells in an HLA-restricted, antigen-specific manner. However, we found that 
      despite the specificity of the soluble Fab, the same antibody in the form of a 
      CAR caused moderate lysis of HLA-A2 expressing targets independent of antigen 
      owing to T cell avidity. We hypothesized that lowering the affinity of the CAR 
      for HLA-A2 would improve its specificity. We undertook a rational approach of 
      mutating residues that, in the crystal structure, were predicted to stabilize 
      binding to HLA-A2. We found that one mutation (DN) lowered the affinity of the 
      Fab to T cell receptor-range and restored the epitope specificity of the CAR. DN 
      CAR T cells lysed native tumor targets in vitro, and, in a xenogeneic mouse model 
      implanted with two human melanoma lines (A2+/NYESO+ and A2+/NYESO-), DN CAR T 
      cells specifically migrated to, and delayed progression of, only the 
      HLA-A2+/NY-ESO-1+ melanoma. Thus, although maintaining MHC-restricted antigen 
      specificity required T cell receptor-like affinity that decreased potency, there 
      is exciting potential for CARs to expand their repertoire to include a broad 
      range of intracellular antigens.
FAU - Maus, Marcela V
AU  - Maus MV
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      New York, USA.
FAU - Plotkin, Jason
AU  - Plotkin J
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      New York, USA.
FAU - Jakka, Gopinadh
AU  - Jakka G
AD  - Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
FAU - Stewart-Jones, Guillaume
AU  - Stewart-Jones G
AD  - Division of Structural Biology, Welcome Trust Centre for Human Genetics, 
      University of Oxford, Oxford, UK.
FAU - Riviere, Isabelle
AU  - Riviere I
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      New York, USA.
FAU - Merghoub, Taha
AU  - Merghoub T
AD  - Ludwig Center for Cancer Immunotherapy, Swim Across America Laboratory, MSKCC, 
      New York, New York, USA.
FAU - Wolchok, Jedd
AU  - Wolchok J
AD  - Ludwig Center for Cancer Immunotherapy, Swim Across America Laboratory, MSKCC, 
      New York, New York, USA.
FAU - Renner, Christoph
AU  - Renner C
AD  - Department of Oncology, University Hospital Zurich, Zurich, Switzerland.
AD  - Department of Oncology, University Hospital Basel, Basel, Switzerland.
FAU - Sadelain, Michel
AU  - Sadelain M
AD  - Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, 
      New York, USA.
AD  - Weill-Cornell Medical College, New York, New York, USA.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
GR  - T32 CA009512/CA/NCI NIH HHS/United States
PT  - Journal Article
DEP - 20170111
PL  - United States
TA  - Mol Ther Oncolytics
JT  - Molecular therapy oncolytics
JID - 101666776
PMC - PMC5904357
EDAT- 2017/01/11 00:00
MHDA- 2017/01/11 00:01
PMCR- 2017/01/11
CRDT- 2018/04/21 06:00
PHST- 2016/04/13 00:00 [received]
PHST- 2016/08/23 00:00 [accepted]
PHST- 2018/04/21 06:00 [entrez]
PHST- 2017/01/11 00:00 [pubmed]
PHST- 2017/01/11 00:01 [medline]
PHST- 2017/01/11 00:00 [pmc-release]
AID - S2372-7705(16)30060-2 [pii]
AID - 16023 [pii]
AID - 10.1038/mto.2016.23 [doi]
PST - epublish
SO  - Mol Ther Oncolytics. 2017 Jan 11;3:1-9. doi: 10.1038/mto.2016.23. eCollection 
      2016.