A phase 1 dose-escalation study of GCC19CART: A novel CAR T-cell therapy for metastatic colorectal cancer in the United States.

3581 Background: GCC19CART, the first clinical candidate of the CoupledCAR solid tumor platform, pairs a solid tumor chimeric antigen receptor (CAR) T-cell with CD19-targeting CAR T-cells. The CD19 target enhances proliferation and persistence of the CoupledCAR, overcoming the limitations seen in other solid tumor CAR T-cells. Guanylate cyclase-C (GCC) is an appealing CAR target due to apical-basal polarity of expression in normal colon, which may hamper on-target effects on the mucosa. GCC is present on nearly all colorectal cancers (CRC). GCC19CART showed promise in a prior trial in China, demonstrating expansion, response, and persistence, consistent with the proposed mechanism. The US phase 1 study was initiated for refractory CRC to assess the safety and efficacy of GCC19CART in this population. Methods: Eligible patients underwent leukapheresis, lymphodepleting chemotherapy (fludarabine 30mg/m 2 and cyclophosphamide 300mg/m 2 on day-3), and a single dose of GCC19CART. Safety was the primary endpoint. Efficacy was assessed by RECIST v1.1 based on local review. Results: As of January 23, 2025, 9 patients were treated: 4 at dose-level (DL) 1 (1x10 6 cells/kg) and 5 at DL2 (2x10 6 cells/kg). Cytokine release syndrome occurred in all subjects (grade [G] 1: 6/9 [66.7%] and G2: 3/9 [33.3%]), and diarrhea was reported in 8/9 (G1: 3/9 [33.3%], G2: 3/9 [33.3%], G3: 2/9 [22.2%]). Immune effector cell associated neurotoxicity syndrome occurred in 2/9 subjects (G2: 1/9 [11.1%], G3: 1/9 [11.1%]). A DL2 patient experienced a dose limiting toxicity (G3 diarrhea, G4 enterocolitis, and G5 sepsis) and died 48 days post-infusion. The overall response rate (ORR) in DL1 was 25% (1/4 partial response [PR]) and 80% in DL2 (4/5 with 3 PR and 1 pathological complete response). The PR in DL1 was achieved by month 2, while 3/4 responders in DL2 achieved a PR by month 1, demonstrating dose-dependent tumor-killing activity. Two DL2 patients maintained responses at data cut-off. One patient achieved a complete metabolic response by PET at month 2 and maintained a PR by CT at month 6 with continuous tumor shrinkage (month 1: 38.33%, month 2: 40.77%, month 4: 82.58%, month 6: 75.61%). Another patient maintained a PR at month 6 with progression at month 8. The median progression-free survival (PFS) was 5.0 months in DL1 and 7.8 months in DL2. The median duration of response was 2.2 months in DL1 and 6.9 months in DL2. Compared to the prior trial in China (≥G3 diarrhea: 22.2% vs. 53.3%; ORR: 66.7% vs. 40%, PFS: 7.8 vs 6.0 months in DL2, 5.0 vs 1.9 in DL1. Chen, JAMA Oncol ., September 2024), the US study suggests a potential trend towards improved safety and efficacy. Conclusions: GCC19CART demonstrated significant clinical activity and durability in refractory CRC. Optimization of diarrhea/colitis management is ongoing. Updated data will be presented. Clinical trial information: NCT05319314 .