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    The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity.

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    10.1007%2Fs00262-017-2034-7.pdf
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    Authors
    Thistlethwaite, Fiona C
    Gilham, David E
    Guest, Ryan D
    Rothwell, Dominic G
    Pillai, Manon
    Burt, Deborah J
    Byatte, Andrea J
    Kirillova, Natalia
    Valle, Juan W
    Sharma, S
    Chester, K
    Westwood, N
    Halford, S
    Nabarro, S
    Wan, S
    Austin, E
    Hawkins, Robert E
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    Affiliation
    Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Wilmslow Road, Withington, Manchester, M20 4BX
    Issue Date
    2017-06-28
    
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    Abstract
    The primary aim of this clinical trial was to determine the feasibility of delivering first-generation CAR T cell therapy to patients with advanced, CEACAM5(+) malignancy. Secondary aims were to assess clinical efficacy, immune effector function and optimal dose of CAR T cells. Three cohorts of patients received increasing doses of CEACAM5(+)-specific CAR T cells after fludarabine pre-conditioning plus systemic IL2 support post T cell infusion. Patients in cohort 4 received increased intensity pre-conditioning (cyclophosphamide and fludarabine), systemic IL2 support and CAR T cells. No objective clinical responses were observed. CAR T cell engraftment in patients within cohort 4 was significantly higher. However, engraftment was short-lived with a rapid decline of systemic CAR T cells within 14 days. Patients in cohort 4 had transient, acute respiratory toxicity which, in combination with lack of prolonged CAR T cell persistence, resulted in the premature closure of the trial. Elevated levels of systemic IFNγ and IL-6 implied that the CEACAM5-specific T cells had undergone immune activation in vivo but only in patients receiving high-intensity pre-conditioning. Expression of CEACAM5 on lung epithelium may have resulted in this transient toxicity. Raised levels of serum cytokines including IL-6 in these patients implicate cytokine release as one of several potential factors exacerbating the observed respiratory toxicity. Whilst improved CAR designs and T cell production methods could improve the systemic persistence and activity, methods to control CAR T 'on-target, off-tissue' toxicity are required to enable a clinical impact of this approach in solid malignancies.
    Citation
    The clinical efficacy of first-generation carcinoembryonic antigen (CEACAM5)-specific CAR T cells is limited by poor persistence and transient pre-conditioning-dependent respiratory toxicity. 2017 Cancer Immunol Immunother
    Journal
    Cancer Immunology, Immunotherapy
    URI
    http://hdl.handle.net/10541/620487
    DOI
    10.1007/s00262-017-2034-7
    PubMed ID
    28660319
    Type
    Article
    Language
    en
    ISSN
    1432-0851
    ae974a485f413a2113503eed53cd6c53
    10.1007/s00262-017-2034-7
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