title: Flexible targeting of ErbB dimers that drive tumorigenesis by using genetically engineered T cells.
abstract: Pharmacological targeting of individual ErbB receptors elicits antitumor activity, but is frequently compromised by resistance leading to therapeutic failure. Here, we describe an immunotherapeutic approach that exploits prevalent and fundamental mechanisms by which aberrant upregulation of the ErbB network drives tumorigenesis. A chimeric antigen receptor named T1E28z was engineered, in which the promiscuous ErbB ligand, T1E, is fused to a CD28 + CD3ζ endodomain. Using a panel of ErbB-engineered 32D hematopoietic cells, we found that human T1E28z⁺ T cells are selectively activated by all ErbB1-based homodimers and heterodimers and by the potently mitogenic ErbB2/3 heterodimer. Owing to this flexible targeting capability, recognition and destruction of several tumor cell lines was achieved by T1E28⁺ T cells in vitro, comprising a wide diversity of ErbB receptor profiles and tumor origins. Furthermore, compelling antitumor activity was observed in mice bearing established xenografts, characterized either by ErbB1/2 or ErbB2/3 overexpression and representative of insidious or rapidly progressive tumor types. Together, these findings support the clinical development of a broadly applicable immunotherapeutic approach in which the propensity of solid tumors to dysregulate the extended ErbB network is targeted for therapeutic gain.
authors.affiliation: King's College London, King's Health Partners Integrated Cancer Center, Department of Research Oncology, Guy's Hospital Campus, London, UK.
authors.forename: David M
authors.initials: DM
authors.lastname: Davies
authors.forename: Julie
authors.initials: J
authors.lastname: Foster
authors.forename: Sjoukje J C
authors.initials: SJ
authors.lastname: Van Der Stegen
authors.forename: Ana C
authors.initials: AC
authors.lastname: Parente-Pereira
authors.forename: Laura
authors.initials: L
authors.lastname: Chiapero-Stanke
authors.forename: George J
authors.initials: GJ
authors.lastname: Delinassios
authors.forename: Sophie E
authors.initials: SE
authors.lastname: Burbridge
authors.forename: Vincent
authors.initials: V
authors.lastname: Kao
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liu
authors.forename: Leticia
authors.initials: L
authors.lastname: Bosshard-Carter
authors.forename: May C I
authors.initials: MC
authors.lastname: Van Schalkwyk
authors.forename: Carol
authors.initials: C
authors.lastname: Box
authors.forename: Suzanne A
authors.initials: SA
authors.lastname: Eccles
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Mather
authors.forename: Scott
authors.initials: S
authors.lastname: Wilkie
authors.forename: John
authors.initials: J
authors.lastname: Maher
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000276:immunology / Q000628:therapy; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D005818:Genetic Engineering; D006258:Head and Neck Neoplasms / Q000276:immunology / Q000628:therapy; D006801:Humans; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D055503:Protein Multimerization / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011946:Receptors, Antigen / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: D015847:Interleukin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D011946:Receptors, Antigen; D011993:Recombinant Fusion Proteins