Imperial College London
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DrKirstyFlower

Faculty of Medicine, Faculty of Medicine Centre

Senior Teaching Fellow
 
 
 
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Contact

 

k.flower Website

 
 
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Location

 

FEO officeSir Alexander Fleming BuildingSouth Kensington Campus

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Summary

 

Publications

Citation

BibTex format

@article{Whilding:2017:10.1016/j.ymthe.2016.10.012,
author = {Whilding, LM and Parente-Pereira, AC and Zabinski, T and Davies, DM and Petrovic, RMG and Kao, YV and Saxena, SA and Romain, A and Costa-Guerra, JA and Violette, S and Itamochi, H and Ghaem-Maghami, S and Vallath, S and Marshall, JF and Maher, J},
doi = {10.1016/j.ymthe.2016.10.012},
journal = {Molecular Therapy},
pages = {259--273},
title = {Targeting of Aberrant alpha v beta 6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells},
url = {http://dx.doi.org/10.1016/j.ymthe.2016.10.012},
volume = {25},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Expression of the αvβ6 integrin is upregulated in several solid tumors. In contrast, physiologic expression of this epithelial-specific integrin is restricted to development and epithelial re-modeling. Here, we describe, for the first time, the development of a chimeric antigen receptor (CAR) that couples the recognition of this integrin to the delivery of potent therapeutic activity in a diverse repertoire of solid tumor models. Highly selective targeting αvβ6 was achieved using a foot and mouth disease virus-derived A20 peptide, coupled to a fused CD28+CD3 endodomain. To achieve selective expansion of CAR T cells ex vivo, an IL-4-responsive fusion gene (4αβ) was co-expressed, which delivers a selective mitogenic signal to engineered T cells only. In vivo efficacy was demonstrated in mice with established ovarian, breast, and pancreatic tumor xenografts, all of which express αvβ6 at intermediate to high levels. SCID beige mice were used for these studies because they are susceptible to cytokine release syndrome, unlike more immune-compromised strains. Nonetheless, although the CAR also engages mouse αvβ6, mild and reversible toxicity was only observed when supra-therapeutic doses of CAR T cells were administered parenterally. These data support the clinical evaluation of αvβ6 re-targeted CAR T cell immunotherapy in solid tumors that express this integrin.
AU  - Whilding,LM
AU  - Parente-Pereira,AC
AU  - Zabinski,T
AU  - Davies,DM
AU  - Petrovic,RMG
AU  - Kao,YV
AU  - Saxena,SA
AU  - Romain,A
AU  - Costa-Guerra,JA
AU  - Violette,S
AU  - Itamochi,H
AU  - Ghaem-Maghami,S
AU  - Vallath,S
AU  - Marshall,JF
AU  - Maher,J
DO  - 10.1016/j.ymthe.2016.10.012
EP  - 273
PY  - 2017///
SN  - 1525-0016
SP  - 259
TI  - Targeting of Aberrant alpha v beta 6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells
T2  - Molecular Therapy
UR  - http://dx.doi.org/10.1016/j.ymthe.2016.10.012
UR  - http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000391901600025&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
UR  - http://hdl.handle.net/10044/1/49361
VL  - 25
ER  -
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