PMID- 25696001
OWN - NLM
STAT- MEDLINE
DCOM- 20151117
LR  - 20230607
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Print)
IS  - 1946-6234 (Linking)
VI  - 7
IP  - 275
DP  - 2015 Feb 18
TI  - Rational development and characterization of humanized anti-EGFR variant III 
      chimeric antigen receptor T cells for glioblastoma.
PG  - 275ra22
LID - 10.1126/scitranslmed.aaa4963 [doi]
AB  - Chimeric antigen receptors (CARs) are synthetic molecules designed to redirect T 
      cells to specific antigens. CAR-modified T cells can mediate long-term durable 
      remissions in B cell malignancies, but expanding this platform to solid tumors 
      requires the discovery of surface targets with limited expression in normal 
      tissues. The variant III mutation of the epidermal growth factor receptor 
      (EGFRvIII) results from an in-frame deletion of a portion of the extracellular 
      domain, creating a neoepitope. We chose a vector backbone encoding a 
      second-generation CAR based on efficacy of a murine scFv-based CAR in a xenograft 
      model of glioblastoma. Next, we generated a panel of humanized scFvs and tested 
      their specificity and function as soluble proteins and in the form of 
      CAR-transduced T cells; a low-affinity scFv was selected on the basis of its 
      specificity for EGFRvIII over wild-type EGFR. The lead candidate scFv was tested 
      in vitro for its ability to direct CAR-transduced T cells to specifically lyse, 
      proliferate, and secrete cytokines in response to antigen-bearing targets. We 
      further evaluated the specificity of the lead CAR candidate in vitro against 
      EGFR-expressing keratinocytes and in vivo in a model of mice grafted with normal 
      human skin. EGFRvIII-directed CAR T cells were also able to control tumor growth 
      in xenogeneic subcutaneous and orthotopic models of human EGFRvIII(+) 
      glioblastoma. On the basis of these results, we have designed a phase 1 clinical 
      study of CAR T cells transduced with humanized scFv directed to EGFRvIII in 
      patients with either residual or recurrent glioblastoma (NCT02209376).
CI  - Copyright (c) 2015, American Association for the Advancement of Science.
FAU - Johnson, Laura A
AU  - Johnson LA
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. 
      Department of Pathology and Laboratory Medicine, Perelman School of Medicine at 
      the University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Scholler, John
AU  - Scholler J
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Ohkuri, Takayuki
AU  - Ohkuri T
AD  - Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
FAU - Kosaka, Akemi
AU  - Kosaka A
AD  - Department of Neurosurgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
FAU - Patel, Prachi R
AU  - Patel PR
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - McGettigan, Shannon E
AU  - McGettigan SE
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Nace, Arben K
AU  - Nace AK
AD  - Department of Dermatology, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Dentchev, Tzvete
AU  - Dentchev T
AD  - Department of Dermatology, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Thekkat, Pramod
AU  - Thekkat P
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Loew, Andreas
AU  - Loew A
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Boesteanu, Alina C
AU  - Boesteanu AC
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Cogdill, Alexandria P
AU  - Cogdill AP
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Chen, Taylor
AU  - Chen T
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Fraietta, Joseph A
AU  - Fraietta JA
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Kloss, Christopher C
AU  - Kloss CC
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Posey, Avery D Jr
AU  - Posey AD Jr
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Engels, Boris
AU  - Engels B
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Singh, Reshma
AU  - Singh R
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Ezell, Tucker
AU  - Ezell T
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Idamakanti, Neeraja
AU  - Idamakanti N
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Ramones, Melissa H
AU  - Ramones MH
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Li, Na
AU  - Li N
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Zhou, Li
AU  - Zhou L
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Plesa, Gabriela
AU  - Plesa G
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Seykora, John T
AU  - Seykora JT
AD  - Department of Dermatology, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Okada, Hideho
AU  - Okada H
AD  - Department of Neurosurgery, University of California, San Francisco, San 
      Francisco, CA 94158, USA.
FAU - June, Carl H
AU  - June CH
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. 
      Department of Pathology and Laboratory Medicine, Perelman School of Medicine at 
      the University of Pennsylvania, Philadelphia, PA 19104, USA.
FAU - Brogdon, Jennifer L
AU  - Brogdon JL
AD  - Novartis Institutes for Biomedical Research, Cambridge, MA 02139, USA.
FAU - Maus, Marcela V
AU  - Maus MV
AD  - Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA. 
      Department of Medicine, Perelman School of Medicine at the University of 
      Pennsylvania, Philadelphia, PA 19104, USA. marcela.maus@uphs.upenn.edu.
LA  - eng
SI  - ClinicalTrials.gov/NCT02209376
GR  - K08-166039/PHS HHS/United States
GR  - R01 CA165836/CA/NCI NIH HHS/United States
GR  - K08 CA166039/CA/NCI NIH HHS/United States
GR  - DP2CA174502/CA/NCI NIH HHS/United States
GR  - DP2 CA174502/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Receptors, Antigen, T-Cell)
RN  - EC 2.7.10.1 (ErbB Receptors)
SB  - IM
CIN - Nat Rev Drug Discov. 2015 Apr;14(4):235. PMID: 25829274
MH  - Animals
MH  - Brain Neoplasms/*therapy
MH  - Disease Models, Animal
MH  - ErbB Receptors/*immunology
MH  - Glioblastoma/*therapy
MH  - Heterografts
MH  - Humans
MH  - *Immunotherapy
MH  - Mice
MH  - Receptors, Antigen, T-Cell/*immunology
PMC - PMC4467166
MID - NIHMS697681
EDAT- 2015/02/20 06:00
MHDA- 2015/11/18 06:00
PMCR- 2016/02/18
CRDT- 2015/02/20 06:00
PHST- 2015/02/20 06:00 [entrez]
PHST- 2015/02/20 06:00 [pubmed]
PHST- 2015/11/18 06:00 [medline]
PHST- 2016/02/18 00:00 [pmc-release]
AID - 7/275/275ra22 [pii]
AID - 10.1126/scitranslmed.aaa4963 [doi]
PST - ppublish
SO  - Sci Transl Med. 2015 Feb 18;7(275):275ra22. doi: 10.1126/scitranslmed.aaa4963.