Phase I study of intraperitoneal fast-manufactured IL-9-secreting CEACAM5-targeted CAR-T cells in advanced colorectal cancer with peritoneal metastases.

Abstract

3514 Background: Colorectal cancer peritoneal metastasis (CRPM) remains an unmet clinical need with poor prognosis and limited benefit from systemic therapies. Our prior study on intraperitoneal (I.P.) CEA-targeting CAR-T cells (Nature Cancer) achieved a 25% ORR, yet limited persistence and exhaustion hampered efficacy. Consequently, we developed a novel Th9/Tc9-polarized fast- manufacturing process that exhibited superior T-cell fitness and antitumor function preclinically. We therefore conducted a Phase I study to evaluate the safety and preliminary efficacy of I.P. administration of these optimized CAR-T cells in CRPM population. Methods: This open-label, single-arm Phase I study enrolled patients with histologically confirmed, heavily pretreated CEA-positive CRPM. A standard 3+3 dose- escalation design evaluated three dose levels (DLs): DL1 (2.0 × 10 5 cells/kg), DL2 (3.0 × 10 5 cells/kg), and DL3 (4.0 × 10 5 cells/kg), followed by dose expansion. Primary objectives were safety and tolerability; secondary objectives included preliminary antitumor activity, cellular kinetics, and pharmacodynamics. Results: Between July 2024 and October 2025, 15 patients were enrolled; 14 were evaluable for efficacy. One dose-limiting toxicity (DLT; Grade 4 pneumonia) occurred at DL2. The most common grade 3 non-hematologic toxicity was diarrhea (53.3%). Cytokine release syndrome (CRS) occurred in all patients and was Grade 1/2 in 93.3%. No treatment-related deaths were reported. Among 14 efficacy-evaluable patients (median 3 prior lines of therapy), ORR was 57.1% and DCR was 100%, with maximum tumor shrinkage reaching 85.6%. Median PFS was 4.7 months (95% CI, 3.7–NE). Peripheral blood CAR- T cells expanded to a mean peak of 1.74×10 4 copies/μg, and serum CEA levels decreased in 100% of patients (median reduction: 67.5%). Conclusions: Intraperitoneal administration of fast-manufactured Th9/Tc9 like CEACAM5-targeted CAR-T cells demonstrated a manageable safety profile and encouraging antitumor activity in heavily pretreated CRPM patients, at approximately one-tenth of conventionally reported CAR-T cell doses. These findings support further development of fitness-enhanced, regionally delivered CAR-T strategies for peritoneal malignancies. Clinical trial information: NCT05396300 . Variable DL1 (n=3) DL2 (n=5) DL3 (n=6) Total (n=14) PR, n (%) 1 (33.3) 4 (80.0) 3 (50.0) 8 (57.1) SD, n (%) 2 (66.7) 1 (20.0) 3 (50.0) 6 (42.9) ORR, n (%) 1 (33.3) 4 (80.0) 3 (50.0) 8 (57.1) DCR, n (%) 3 (100.0) 5 (100.0) 6 (100.0) 14 (100.0) Median PFS, months 5.6 [3.8–NE] 3.4 [3.2–NE] NA 4.7 [3.4–NE]