Hypoxia-responsive CEA-targeted CAR T cells in CEA-positive solid tumors through intraperitoneal or intravenous infusion: a phase 1 trial.

Chimeric antigen receptor (CAR) T cell therapy for solid tumors remains challenging. This phase 1, open-label, dose-escalation and expansion study (ClinicalTrials.gov registration: NCT05396300 ) evaluated the safety and efficacy of PC13, a hypoxia-responsive, carcinoembryonic antigen (CEA)-targeted CAR T cell therapy, in persons with CEA-positive solid tumors. The primary endpoint was safety; secondary endpoints included efficacy, pharmacokinetics and pharmacodynamics. A total of 43 heavily pretreated participants (46.5% with ≥4 prior lines) were assigned to receive PC13 through intraperitoneal (I.P., n = 17) or intravenous (I.V., n = 26) infusion on the basis of predominant metastatic sites. Grade 3 diarrhea occurred in 20.9% of participants and 76.7% experienced grade 1 or 2 cytokine release syndrome. Disease control rates were 82.4% in the I.P. group and 68.0% in the I.V. group, with objective response rates (ORRs) of 23.5% and 8.0%, respectively. In post hoc analyses, ORRs reached 57.1% (4/7) in the I.P. group with peritoneal metastases and 40.0% (2/5) in the I.V. group without liver metastases, both among participants with CEA immunohistochemistry expression ≥ 90%. The predefined safety endpoint was met. PC13 demonstrated manageable toxicity and promising efficacy, supporting further investigations.