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Targeting of Aberrant alpha v beta 6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells

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Title: Targeting of Aberrant alpha v beta 6 Integrin Expression in Solid Tumors Using Chimeric Antigen Receptor-Engineered T Cells
Authors: Whilding, LM
Parente-Pereira, AC
Zabinski, T
Davies, DM
Petrovic, RMG
Kao, YV
Saxena, SA
Romain, A
Costa-Guerra, JA
Violette, S
Itamochi, H
Ghaem-Maghami, S
Vallath, S
Marshall, JF
Maher, J
Item Type: Journal Article
Abstract: 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.
Issue Date: 4-Jan-2017
Date of Acceptance: 6-Oct-2016
URI: http://hdl.handle.net/10044/1/49361
DOI: https://dx.doi.org/10.1016/j.ymthe.2016.10.012
ISSN: 1525-0016
Publisher: Elsevier
Start Page: 259
End Page: 273
Journal / Book Title: Molecular Therapy
Volume: 25
Issue: 1
Copyright Statement: © 2016 The American Society of Gene and Cell Therapy. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor/Funder: US Army (US)
Imperial College Healthcare NHS Trust- BRC Funding
Medical Research Council (MRC)
Funder's Grant Number: W81XWH-09-1-0097
RDB01 79560
RTJ9793241-1
Keywords: Science & Technology
Life Sciences & Biomedicine
Biotechnology & Applied Microbiology
Genetics & Heredity
Medicine, Research & Experimental
Research & Experimental Medicine
MOUTH-DISEASE-VIRUS
EPITHELIAL OVARIAN-CANCER
SQUAMOUS CARCINOMA-CELLS
IN-VIVO
UP-REGULATION
ANTIBODY
INTEGRIN-ALPHA(V)BETA(6)
INVASION
GROWTH
SPECIFICITY
Immunotherapy
cancer
chimeric antigen receptor
solid tumor
αvβ6
Animals
Antigens, Neoplasm
Cell Engineering
Cytokines
Disease Models, Animal
Gene Expression
Gene Order
Genetic Vectors
Immunotherapy, Adoptive
Integrins
Lymphocyte Subsets
Mice
Mice, SCID
Neoplasms
Receptors, Antigen, T-Cell
Recombinant Fusion Proteins
Xenograft Model Antitumor Assays
06 Biological Sciences
10 Technology
11 Medical And Health Sciences
Biotechnology
Publication Status: Published
Appears in Collections:Division of Surgery
Division of Cancer



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