PMID- 23926201
OWN - NLM
STAT- MEDLINE
DCOM- 20140519
LR  - 20231120
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 5
IP  - 197
DP  - 2013 Aug 7
TI  - Identification of a Titin-derived HLA-A1-presented peptide as a cross-reactive 
      target for engineered MAGE A3-directed T cells.
PG  - 197ra103
LID - 10.1126/scitranslmed.3006034 [doi]
AB  - MAGE A3, which belongs to the family of cancer-testis antigens, is an attractive 
      target for adoptive therapy given its reactivation in various tumors and limited 
      expression in normal tissues. We developed an affinity-enhanced T cell receptor 
      (TCR) directed to a human leukocyte antigen (HLA)-A*01-restricted MAGE A3 antigen 
      (EVDPIGHLY) for use in adoptive therapy. Extensive preclinical investigations 
      revealed no off-target antigen recognition concerns; nonetheless, administration 
      to patients of T cells expressing the affinity-enhanced MAGE A3 TCR resulted in a 
      serious adverse event (SAE) and fatal toxicity against cardiac tissue. We present 
      a description of the preclinical in vitro functional analysis of the MAGE A3 TCR, 
      which failed to reveal any evidence of off-target activity, and a full analysis 
      of the post-SAE in vitro investigations, which reveal cross-recognition of an 
      off-target peptide. Using an amino acid scanning approach, a peptide from the 
      muscle protein Titin (ESDPIVAQY) was identified as an alternative target for the 
      MAGE A3 TCR and the most likely cause of in vivo toxicity. These results 
      demonstrate that affinity-enhanced TCRs have considerable effector functions in 
      vivo and highlight the potential safety concerns for TCR-engineered T cells. 
      Strategies such as peptide scanning and the use of more complex cell cultures are 
      recommended in preclinical studies to mitigate the risk of off-target toxicity in 
      future clinical investigations.
FAU - Cameron, Brian J
AU  - Cameron BJ
AD  - Immunocore Ltd., 57c Milton Park, Jubilee Avenue, Abingdon, OX14 4RX, UK.
FAU - Gerry, Andrew B
AU  - Gerry AB
FAU - Dukes, Joseph
AU  - Dukes J
FAU - Harper, Jane V
AU  - Harper JV
FAU - Kannan, Vivekanandan
AU  - Kannan V
FAU - Bianchi, Frayne C
AU  - Bianchi FC
FAU - Grand, Francis
AU  - Grand F
FAU - Brewer, Joanna E
AU  - Brewer JE
FAU - Gupta, Minnal
AU  - Gupta M
FAU - Plesa, Gabriela
AU  - Plesa G
FAU - Bossi, Giovanna
AU  - Bossi G
FAU - Vuidepot, Annelise
AU  - Vuidepot A
FAU - Powlesland, Alex S
AU  - Powlesland AS
FAU - Legg, Alison
AU  - Legg A
FAU - Adams, Katherine J
AU  - Adams KJ
FAU - Bennett, Alan D
AU  - Bennett AD
FAU - Pumphrey, Nicholas J
AU  - Pumphrey NJ
FAU - Williams, Daniel D
AU  - Williams DD
FAU - Binder-Scholl, Gwendolyn
AU  - Binder-Scholl G
FAU - Kulikovskaya, Irina
AU  - Kulikovskaya I
FAU - Levine, Bruce L
AU  - Levine BL
FAU - Riley, James L
AU  - Riley JL
FAU - Varela-Rohena, Angel
AU  - Varela-Rohena A
FAU - Stadtmauer, Edward A
AU  - Stadtmauer EA
FAU - Rapoport, Aaron P
AU  - Rapoport AP
FAU - Linette, Gerald P
AU  - Linette GP
FAU - June, Carl H
AU  - June CH
FAU - Hassan, Namir J
AU  - Hassan NJ
FAU - Kalos, Michael
AU  - Kalos M
FAU - Jakobsen, Bent K
AU  - Jakobsen BK
LA  - eng
GR  - P01 CA214278/CA/NCI NIH HHS/United States
GR  - U19 AI082628/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Connectin)
RN  - 0 (HLA-A1 Antigen)
RN  - 0 (MAGEA3 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Peptides)
RN  - 0 (Receptors, Antigen, T-Cell)
SB  - IM
MH  - Amino Acid Sequence
MH  - Antigen Presentation/*immunology
MH  - Antigens, Neoplasm/chemistry/*immunology
MH  - Antineoplastic Agents/pharmacology
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Connectin/*chemistry/immunology
MH  - Cross Reactions/drug effects/*immunology
MH  - HEK293 Cells
MH  - HLA-A1 Antigen/*immunology
MH  - Humans
MH  - Lymphocyte Activation/drug effects
MH  - Molecular Sequence Data
MH  - Myocytes, Cardiac/drug effects/metabolism
MH  - Neoplasm Proteins/chemistry/*immunology
MH  - Peptides/chemistry/*immunology
MH  - Protein Engineering
MH  - Receptors, Antigen, T-Cell/metabolism
MH  - T-Lymphocytes/drug effects/*metabolism
PMC - PMC6002776
MID - NIHMS958713
COIS- Competing interests: B.J.C., J.D., J.V.H., V.K., F.C.B., F.G., G.B., A.V., 
      A.S.P., A.L., N.J.H., and B.K.J. are employees of Immunocore Ltd. A.B.G., J.E.B., 
      K.J.A., A.D.B., N.J.P., D.D.W., G.B.-S., and B.K.J. are employees of Adaptimmune 
      Ltd. A patent has been filed on the sequence and utility of the TCRs used in this 
      study (WO12/03913). The remaining authors declare no competing interests.
EDAT- 2013/08/09 06:00
MHDA- 2014/05/20 06:00
PMCR- 2018/06/15
CRDT- 2013/08/09 06:00
PHST- 2013/08/09 06:00 [entrez]
PHST- 2013/08/09 06:00 [pubmed]
PHST- 2014/05/20 06:00 [medline]
PHST- 2018/06/15 00:00 [pmc-release]
AID - 5/197/197ra103 [pii]
AID - 10.1126/scitranslmed.3006034 [doi]
PST - ppublish
SO  - Sci Transl Med. 2013 Aug 7;5(197):197ra103. doi: 10.1126/scitranslmed.3006034.