PMID- 23939024
OWN - NLM
STAT- MEDLINE
DCOM- 20140624
LR  - 20220310
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 21
IP  - 11
DP  - 2013 Nov
TI  - Combinational targeting offsets antigen escape and enhances effector functions of 
      adoptively transferred T cells in glioblastoma.
PG  - 2087-101
LID - 10.1038/mt.2013.185 [doi]
AB  - Preclinical and early clinical studies have demonstrated that chimeric antigen 
      receptor (CAR)-redirected T cells are highly promising in cancer therapy. We 
      observed that targeting HER2 in a glioblastoma (GBM) cell line results in the 
      emergence of HER2-null tumor cells that maintain the expression of nontargeted 
      tumor-associated antigens. Combinational targeting of these tumor-associated 
      antigens could therefore offset this escape mechanism. We studied the single-cell 
      coexpression patterns of HER2, IL-13Ralpha2, and EphA2 in primary GBM samples using 
      multicolor flow cytometry and immunofluorescence, and applied a binomial routine 
      to the permutations of antigen expression and the related odds of complete tumor 
      elimination. This mathematical model demonstrated that cotargeting HER2 and 
      IL-13Ralpha2 could maximally expand the therapeutic reach of the T cell product in 
      all primary tumors studied. Targeting a third antigen did not predict an added 
      advantage in the tumor cohort studied. We therefore generated bispecific T cell 
      products from healthy donors and from GBM patients by pooling T cells 
      individually expressing HER2 and IL-13Ralpha2-specific CARs and by making individual 
      T cells to coexpress both molecules. Both HER2/IL-13Ralpha2-bispecific T cell 
      products offset antigen escape, producing enhanced effector activity in vitro 
      immunoassays (against autologous glioma cells in the case of GBM patient 
      products) and in an orthotopic xenogeneic murine model. Further, T cells 
      coexpressing HER2 and IL-13Ralpha2-CARs exhibited accentuated yet antigen-dependent 
      downstream signaling and a particularly enhanced antitumor activity.
FAU - Hegde, Meenakshi
AU  - Hegde M
AD  - 1] Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, Texas, 
      USA [2] Texas Children's Cancer Center, Baylor College of Medicine, Houston, 
      Texas, USA [3] Department of Pediatrics, Baylor College of Medicine, Houston, 
      Texas, USA.
FAU - Corder, Amanda
AU  - Corder A
FAU - Chow, Kevin K H
AU  - Chow KK
FAU - Mukherjee, Malini
AU  - Mukherjee M
FAU - Ashoori, Aidin
AU  - Ashoori A
FAU - Kew, Yvonne
AU  - Kew Y
FAU - Zhang, Yi Jonathan
AU  - Zhang YJ
FAU - Baskin, David S
AU  - Baskin DS
FAU - Merchant, Fatima A
AU  - Merchant FA
FAU - Brawley, Vita S
AU  - Brawley VS
FAU - Byrd, Tiara T
AU  - Byrd TT
FAU - Krebs, Simone
AU  - Krebs S
FAU - Wu, Meng Fen
AU  - Wu MF
FAU - Liu, Hao
AU  - Liu H
FAU - Heslop, Helen E
AU  - Heslop HE
FAU - Gottschalk, Stephen
AU  - Gottschalk S
FAU - Yvon, Eric
AU  - Yvon E
FAU - Ahmed, Nabil
AU  - Ahmed N
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - 5T32GM007330/GM/NIGMS NIH HHS/United States
GR  - CA16672/CA/NCI NIH HHS/United States
GR  - T32 HL092332/HL/NHLBI NIH HHS/United States
GR  - P30CA125123/CA/NCI NIH HHS/United States
GR  - T32 DK064717/DK/NIDDK NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
GR  - P01 CA094237/CA/NCI NIH HHS/United States
GR  - T32 GM007330/GM/NIGMS NIH HHS/United States
GR  - 5T32HL092332/HL/NHLBI NIH HHS/United States
GR  - T32 GM088129/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130813
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Interleukin-13 Receptor alpha2 Subunit)
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - 0 (Recombinant Fusion Proteins)
RN  - EC 2.7.10.1 (Receptor, ErbB-2)
SB  - IM
EIN - Mol Ther. 2014 May;22(5):1063. Gottachalk, Stephen [corrected to Gottschalk, 
      Stephen]
MH  - *Adoptive Transfer
MH  - Animals
MH  - Antigens, Neoplasm/genetics/immunology/*metabolism
MH  - Cell Line, Tumor
MH  - Combined Modality Therapy
MH  - Glioblastoma/immunology/pathology/*therapy
MH  - HEK293 Cells
MH  - Humans
MH  - Interleukin-13 Receptor alpha2 Subunit/genetics/immunology/metabolism
MH  - Mice
MH  - Mice, SCID
MH  - Models, Biological
MH  - Receptor, ErbB-2/genetics/immunology/metabolism
MH  - Receptors, Antigen, T-Cell/immunology/*metabolism
MH  - Recombinant Fusion Proteins/immunology/metabolism
MH  - T-Lymphocytes/*immunology
MH  - Tumor Cells, Cultured
MH  - Tumor Escape
MH  - Xenograft Model Antitumor Assays
PMC - PMC3831041
EDAT- 2013/08/14 06:00
MHDA- 2014/06/25 06:00
PMCR- 2013/11/01
CRDT- 2013/08/14 06:00
PHST- 2013/01/18 00:00 [received]
PHST- 2013/07/30 00:00 [accepted]
PHST- 2013/08/14 06:00 [entrez]
PHST- 2013/08/14 06:00 [pubmed]
PHST- 2014/06/25 06:00 [medline]
PHST- 2013/11/01 00:00 [pmc-release]
AID - S1525-0016(16)30931-5 [pii]
AID - 10.1038/mt.2013.185 [doi]
PST - ppublish
SO  - Mol Ther. 2013 Nov;21(11):2087-101. doi: 10.1038/mt.2013.185. Epub 2013 Aug 13.