Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T-cells

Lynsey M. Whilding; Ana C. Parente Pereira; Tomasz Zabinski; David M. Davies; Roseanna Petrovic; Vincent Kao; Shobhit A Saxena; Alex Romain; Jose A Costa-Guerra; Shelia Violette; Hiroaki Itamochi; Sadaf Ghaem-Maghami; Sabari Vallath; John F Marshall; John Maher

doi:10.1016/j.ymthe.2016.10.012

Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T-cells

Lynsey M. Whilding, Ana C. Parente Pereira, Tomasz Zabinski, David M. Davies, Roseanna Petrovic, Vincent Kao, Shobhit A Saxena, Alex Romain, Jose A Costa-Guerra, Shelia Violette, Hiroaki Itamochi, Sadaf Ghaem-Maghami, Sabari Vallath, John F Marshall, John Maher

Comprehensive Cancer Centre

King's College London

Research output: Contribution to journal › Article › peer-review

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Abstract

Expression of the αvβ6 integrin is upregulated in several solid tumors. By 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 of 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 since 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.

Original language	English
Pages (from-to)	259-273
Journal	Molecular Therapy
Volume	25
Issue number	1
Early online date	4 Jan 2017
DOIs	https://doi.org/10.1016/j.ymthe.2016.10.012
Publication status	Published - 4 Jan 2017

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Whilding, L. M., Parente Pereira, A. C., Zabinski, T., Davies, D. M., Petrovic, R., Kao, V., Saxena, S. A., Romain, A., Costa-Guerra, J. A., Violette, S., Itamochi, H., Ghaem-Maghami, S., Vallath, S., Marshall, J. F., & Maher, J. (2017). Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T-cells. Molecular Therapy, 25(1), 259-273. https://doi.org/10.1016/j.ymthe.2016.10.012

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title = "Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T-cells",

abstract = "Expression of the αvβ6 integrin is upregulated in several solid tumors. By 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 of 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 since 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.",

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Whilding, LM , Parente Pereira, AC, Zabinski, T, Davies, DM, Petrovic, R, Kao, V, Saxena, SA, Romain, A, Costa-Guerra, JA, Violette, S, Itamochi, H, Ghaem-Maghami, S, Vallath, S, Marshall, JF & Maher, J 2017, 'Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T-cells', Molecular Therapy, vol. 25, no. 1, pp. 259-273. https://doi.org/10.1016/j.ymthe.2016.10.012

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AU - Whilding, Lynsey M.

AU - Parente Pereira, Ana C.

AU - Zabinski, Tomasz

AU - Davies, David M.

AU - Petrovic, Roseanna

AU - Kao, Vincent

AU - Saxena, Shobhit A

AU - Romain, Alex

AU - Costa-Guerra, Jose A

AU - Violette, Shelia

AU - Itamochi, Hiroaki

AU - Ghaem-Maghami, Sadaf

AU - Vallath, Sabari

AU - Marshall, John F

AU - Maher, John

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N2 - Expression of the αvβ6 integrin is upregulated in several solid tumors. By 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 of 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 since 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.

AB - Expression of the αvβ6 integrin is upregulated in several solid tumors. By 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 of 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 since 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.

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DO - 10.1016/j.ymthe.2016.10.012

M3 - Article

SN - 1525-0016

VL - 25

SP - 259

EP - 273

JO - Molecular Therapy

JF - Molecular Therapy

IS - 1

ER -

Targeting of aberrant αvβ6 integrin expression in solid tumors using chimeric antigen receptor-engineered T-cells

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