Fiona C. Thistlethwaite , 1 , 2 , David E. Gilham 2 , Ryan D. Guest 2 , 7 , Dominic G. Rothwell 3 , Manon Pillai 1 , 2 , Deborah J. Burt 3 , Andrea J. Byatte 1 , Natalia Kirillova 2 , 7 , Juan W. Valle 1 , 2 , Surinder K. Sharma 4 , Kerry A. Chester 4 , Nigel B. Westwood 5 , Sarah E. R. Halford 5 , Stephen Nabarro 5 , Susan Wan 5 , Eric Austin 6 , Robert E. Hawkins 1 , 2
28 June 2017
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.