Guanylyl Cyclase 2C-Targeted Chimeric Antigen Receptor T-Cell Therapy in Patients With Metastatic Colorectal Cancer

The clinical efficacies of third- or later-line therapies for metastatic colorectal cancer (CRC) are extremely limited. The purpose of this study was to evaluate the safety and efficacy of a chimeric antigen receptor T (CAR T) cell targeting guanylyl cyclase 2C (GUCY2C) that was steadily expressed in all stages of CRC in a phase I study.

This was an open-label, single-center, phase I study, consisting of a 3 + 3 pattern dose-escalation phase and a dose-expansion investigation. Tumor tissues were histologically confirmed positive for GUCY2C expression. Four dose levels were tested in the dose-escalation phase, including 3 × 10⁸ (DL1), 6 × 10⁸ (DL2), 12 × 10⁸ (DL3), and 20 × 10⁸ (DL4) CAR T cells. The primary end points were safety and tolerability within 28 days after the first infusion.

In the dose-escalation phase, dose-limiting toxicity was not observed. DL3 was chosen for dose-expansion study. A total of 20 patients with metastatic CRC were infused with GUCY2C CAR T after lymphodepletion, and only one patient (5.0%) showed grade 3 cytokine release syndrome and neurotoxicity. Grade 3 diarrhea occurred in 11 patients (55.0%). Of 19 evaluable patients, the objective response rate (ORR) was 26.3%, with all responding patients in DL3 and DL4 groups. Of 10 patients in the DL3 group, the ORR was 40.0% and the median progression-free survival time (mPFS) was 7.0 months. Among patients showing medium-to-high GUCY2C expression in the DL3 group, the ORR achieved 50.0% and the mPFS was 9.0 months.

GUCY2C CAR T showed acceptable safety profile and high response rate in patients with third- or later-line CRC, and the clinical efficacy was associated with CAR T dose level.