Nonarmored GCC-Targeting CAR T-cell Therapy Demonstrates Significant Efficacy in Patients with Advanced Colorectal Cancer

Abstract Purpose: This phase I clinical trial aims to evaluate the safety, expansion kinetics, and preliminary efficacy of nonarmored, nanobody-derived guanylyl cyclase 2C (GCC)–targeted chimeric antigen receptor (CAR) T cells in patients with heavily pretreated metastatic colorectal cancer. Patients and Methods: In this single-arm, open-label, phase I clinical trial, 24 patients who received at least 2 prior lines of treatment received GCC-targeted CAR T cells across 4 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: 1 due to immune effector cell–associated hemophagocytic lymphohistiocytosis–like syndrome and 1 due to intestinal fistula following rapid tumor regression in a lesion adherent to the intestinal wall. The objective response rate and disease control rate reached 33% and 63%, respectively. Eight patients achieved a partial response as their best response, 7 maintained stable disease, and 5 had progressive disease. Median progression-free survival was 57 days, and median overall survival was 190 days. Higher in vivo CAR T-cell 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 patients with colorectal cancer, 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.