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Cancer Immunol Immunother. 2017 Nov;66(11):1425-1436. doi: 10.1007/s00262-017-2034-7. Epub 2017 Jun 28.

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.

Author information

1
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Wilmslow Road, Withington, Manchester, M20 4BX, UK. fiona.thistlethwaite@christie.nhs.uk.
2
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Healthcare Science Centre, Wilmslow Road, Withington, Manchester, UK. fiona.thistlethwaite@christie.nhs.uk.
3
Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Healthcare Science Centre, Wilmslow Road, Withington, Manchester, UK.
4
Cellular Therapeutics Limited, Grafton Street, Manchester, UK.
5
Clinical and Experimental Pharmacology Group, Cancer Research UK Manchester Institute, The University of Manchester, Wilmslow Road, Withington, Manchester, UK.
6
Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester Academic Health Science Centre, Wilmslow Road, Withington, Manchester, M20 4BX, UK.
7
University College London (UCL) Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, UK.
8
Cancer Research UK Centre for Drug Development, Angel Building, 407 St John Street, London, UK.
9
Stem Cells and Immunotherapy, National Health Service Blood and Transplant (NHSBT) Liverpool Centre, Speke, Liverpool, UK.

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.

KEYWORDS:

CEA; Chimeric antigen receptor; Persistence; T cells; Toxicity

PMID:
28660319
PMCID:
PMC5645435
DOI:
10.1007/s00262-017-2034-7
[Indexed for MEDLINE]
Free PMC Article

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