title: Intracavitary 'T4 immunotherapy' of malignant mesothelioma using pan-ErbB re-targeted CAR T-cells.
abstract: Malignant mesothelioma remains an incurable cancer. We demonstrated that mesotheliomas expressed EGFR (79.2%), ErbB4 (49.0%) and HER2 (6.3%), but lacked ErbB3. At least one ErbB family member was expressed in 88% of tumors. To exploit ErbB dysregulation in this disease, patient T-cells were engineered by retroviral transduction to express a panErbB-targeted chimeric antigen receptor (CAR), co-expressed with a chimeric cytokine receptor that allows interleukin (IL)-4 mediated CAR T-cell proliferation. This combination is referred to as T4 immunotherapy. T-cells from mesothelioma patients were uniformly amenable to T4 genetic modification and expansion/enrichment thereafter using IL-4. Patient-derived T4+T-cells were activated upon contact with a panel of four mesothelioma cell lines, leading to cytotoxicity and cytokine release in all cases. Adoptive transfer of T4 immunotherapy to SCID Beige mice with an established bioluminescent LO68 mesothelioma xenograft was followed by regression or eradication of disease in all animals. Despite the established ability of T4 immunotherapy to elicit cytokine release syndrome in SCID Beige mice, therapy was very well tolerated. These findings provide a strong rationale for the clinical evaluation of intracavitary T4 immunotherapy to treat mesothelioma.
authors.affiliation: King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Astero
authors.initials: A
authors.lastname: Klampatsa
authors.affiliation: King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Daniela Y
authors.initials: DY
authors.lastname: Achkova
authors.affiliation: King's College London, 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, 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, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Natalie
authors.initials: N
authors.lastname: Woodman
authors.affiliation: King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: James
authors.initials: J
authors.lastname: Rosekilly
authors.affiliation: Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Georgina
authors.initials: G
authors.lastname: Osborne
authors.affiliation: King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK.
authors.forename: Thivyan
authors.initials: T
authors.lastname: Thayaparan
authors.affiliation: Department of Thoracic Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bille
authors.affiliation: Department of Histopathology, Barts Health NHS Trust, The Royal London Hospital, London E1 2ES, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Sheaf
authors.affiliation: King's College London, Division of Cancer Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, UK; Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: James F
authors.initials: JF
authors.lastname: Spicer
authors.affiliation: Department of Thoracic Surgery, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: Juliet
authors.initials: J
authors.lastname: King
authors.affiliation: King's College London, 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; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D016513:Mice, SCID; D010997:Pleural Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D066247:Receptor, ErbB-4 / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D013997:Time Factors; D014161:Transduction, Genetic; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: D066246:ErbB Receptors; D015847:Interleukin-4; D018719:Erb-b2 Receptor Tyrosine Kinases; D066247:Receptor, ErbB-4; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; C508598:IL4 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C587689:ERBB4 protein, human
keywords: Chimeric antigen receptor; Epidermal growth factor receptor; Lung cancer; Mesothelioma