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

Fiona Thistlethwaite, David Gilham, Ryan Guest, Dominic Rothwell, Manon Pillai, Deborah Burt, Andrea J Byatte, Natalia Kirillova, Juan Valle, Surinder K Sharma , Kerry A. Chester, Nigel Westwood, Sarah ER Halford, Stephen Nabarro, Susan Wan, Eric Austin, Robert E Hawkins

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
JournalCancer Immunology, Immunotherapy
Early online date28 Jun 2017
DOIs
Publication statusPublished - 2017

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre

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