Non-Armored GCC-targeting CAR-T cell therapy demonstrates significant efficacy in patients with advanced colorectal cancer

PURPOSE: This phase 1 clinical trial aims to evaluate the safety, expansion kinetics, and preliminary efficacy of non-armored, nanobody-derived GCC-targeted CAR-T cells in patients with heavily pretreated, metastatic colorectal cancer. PATIENTS AND METHODS: In this single-arm, open-label, phase 1 clinical trial, twenty-four patients who received at least two prior lines of treatment received GCC-targeted CAR-T cells across four dose levels: 0.5×105, 1×106, 2×106,and 3×106 CAR-T cells/kg. The primary endpoint was safety; secondary endpoints included antitumor activity and pharmacokinetics. RESULTS: All patients experienced grade 3 or higher hematologic toxicity, and 75% developed cytokine release syndrome, both of which were generally manageable. Two treatment-related deaths occurred, one due to immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome and one due to intestinal fistula following rapid tumor regression in a lesion adherent to the intestinal wall. The overall response rate (ORR) and disease control rate (DCR) reached 33% and 63%, respectively. Eight patients achieved a partial response (PR) as their best response, seven maintained stable disease (SD), and five had progressive disease (PD). Median progression-free survival (mPFS) was 57 days and median overall survival (mOS) was 190 days. Higher in vivo CAR-T expansion was associated with better disease control. Proof-of-concept activity was demonstrated, although response durability was limited and toxicity remains challenging. CONCLUSIONS: GCC-targeted CAR-T cells demonstrated encouraging antitumor activity in heavily pretreated CRC patients, with the initial data supporting GCC as a clinically actionable target. Further development will require dose selection, patient eligibility, and toxicity management optimization to improve the therapeutic profile.