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. 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.
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Lynsey M
authors.initials: LM
authors.lastname: Whilding
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Parente-Pereira
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zabinski
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Davies
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Roseanna M G
authors.initials: RMG
authors.lastname: Petrovic
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Y Vincent
authors.initials: YV
authors.lastname: Kao
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Shobhit A
authors.initials: SA
authors.lastname: Saxena
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Alex
authors.initials: A
authors.lastname: Romain
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Jose A
authors.initials: JA
authors.lastname: Costa-Guerra
authors.affiliation: Biogen Idec, Cambridge, MA 02142, USA.
authors.forename: Shelia
authors.initials: S
authors.lastname: Violette
authors.affiliation: Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Iwate 020-8505, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Itamochi
authors.affiliation: Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK.
authors.forename: Sadaf
authors.initials: S
authors.lastname: Ghaem-Maghami
authors.affiliation: Centre for Tumour Biology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: Sabari
authors.initials: S
authors.lastname: Vallath
authors.affiliation: Centre for Tumour Biology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
authors.forename: John F
authors.initials: JF
authors.lastname: Marshall
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Centre and Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Department of Clinical Immunology and Allergy, King's College Hospital NHS Foundation Trust, Denmark Hill, London SE5 9RS, UK; Department of Immunology, Eastbourne Hospital, Kings Drive, Eastbourne, East Sussex BN21 2UD, UK. Electronic address: john.maher@kcl.ac.uk.
authors.forename: John
authors.initials: J
authors.lastname: Maher
mesh_terms: D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics / Q000276:immunology*; D060846:Cell Engineering; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D023061:Gene Order; D005822:Genetic Vectors / Q000235:genetics; D016219:Immunotherapy, Adoptive; D016023:Integrins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism* / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000951:Antigens, Neoplasm; D016207:Cytokines; D016023:Integrins; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C073878:integrin alphavbeta6
keywords: Immunotherapy; cancer; chimeric antigen receptor; solid tumor; αvβ6