Phase I Hepatic Immunotherapy for Metastases Study of Intra-Arterial Chimeric Antigen Receptor-Modified T-cell Therapy for CEA+ Liver Metastases.

PURPOSE: Chimeric antigen receptor modified T cells (CAR-T) have demonstrated encouraging results in early-phase clinical trials. Successful adaptation of CAR-T technology for CEA-expressing adenocarcinoma liver metastases (LM), a major cause of death in patients with gastrointestinal cancers, has yet to be achieved. We sought to test intrahepatic delivery of anti-CEA CAR-T through percutaneous hepatic artery infusions (HAI). EXPERIMENTAL DESIGN: We conducted a phase I trial to test HAI of CAR-T in patients with CEA+ LM. Six patients completed the protocol, and 3 received anti-CEA CAR-T HAIs alone in dose-escalation fashion (10(8), 10(9), and 10(10) cells). We treated an additional 3 patients with the maximum planned CAR-T HAI dose (10(10) cells X 3) along with systemic IL2 support. RESULTS: Four patients had more than 10 LM and patients received a mean of 2.5 lines of conventional systemic therapy prior to enrollment. No patient suffered a grade 3 or 4 adverse event related to the CAR-T HAIs. One patient remains alive with stable disease at 23 months following CAR-T HAI and 5 patients died of progressive disease. Among the patients in the cohort that received systemic IL2 support, CEA levels decreased 37% (range 19–48%) from baseline. Biopsies demonstrated an increase in LM necrosis or fibrosis in 4 of 6 patients. Elevated serum IFNγ levels correlated with IL2 administration and CEA decreases. CONCLUSIONS: We have demonstrated the safety of anti-CEA CAR-T HAIs with encouraging signals of clinical activity in a heavily pre-treated population with large tumor burdens. Further clinical testing of CAR-T HAIs for LM is warranted