A phase 1 dose escalation study of a novel coupled CAR T cell therapy, GCC19CART, for patients with metastatic colorectal cancer.

e15572 Background: GCC19CART is a multitargeted CAR-T cell therapy designed to overcome the limitations of conventional CAR-T cells in solid malignancies by pairing a solid tumor targeting CAR with additional CD19-targeting CARs. This addition is meant to amplify proliferation, activation, and persistence of the CAR-T cells with a goal to overcome the inherent resistance of solid tumors to CAR-T cells. Guanylate cyclase-C (GCC) has been reported to be expressed in over 80% of colorectal cancers with normal expression largely restricted to the luminal side of the GI tract, making it an appealing target for CAR-T cell therapy. A Phase 1 investigator-initiated clinical trial in China reported preliminary results with an ORR of 15.4% (2/13), mOS of 13.3 months in dose level 1 (1x10 6 CAR-T cells/kg) and 50% (4/8), mOS of 26.1 months in dose level 2 (2x10 6 CAR-T cells/kg). Common adverse events included cytokine release syndrome (CRS), diarrhea/colitis, and immune effector cell-associated neurotoxicity syndrome (ICANS). Methods: A phase 1 study in the United States was initiated in August, 2022, for patients with refractory metastatic colorectal cancer. As of a data cutoff of December 31, 2023, with a prespecified analysis after the DLT window for the first patient treated at dose level 2, 5 subjects have been reinfused: 4 in dose level 1 and 1 in dose level 2. Subjects were screened for GCC expression. Over 95% of participants screened positive, so this requirement was removed. Eligible subjects underwent leukapheresis, lymphodepleting chemotherapy with a single dose of fludarabine 30mg/m 2 and cyclophosphamide 300mg/m 2 , and infusion of GCC19CART. Responses were assessed by RECIST v1.1 by site investigator and an independent third-party imaging review. Results: Five subjects have been treated, 4 in dose level 1 (1x10 6 cells/kg) and 1 in dose level 2 (2x10 6 cells/kg), and have completed the 30 day DLT period. The most common CAR-T related adverse events were CRS in 5/5 subjects (grade 1: 2/5 (40%) and grade 2: 3/5 (60%)), diarrhea in 4/5 subjects (grade 1: 1/5 (20%), grade 2: 2/5 (40%), and grade 3: 1/5 (20%)), and ICANS (grade 2: 1/5 (20%)). All adverse events resolved with therapy. The ORR was 40% (2/5) by independent review: 2 subjects demonstrated a partial response however 1 additional subject had partial metabolic response on PET/CT with stable disease. Progressive disease was seen in 2 participants by RECIST 1.1, but 1 has a falling tumor marker suggesting tumor flare. Conclusions: Preliminary results demonstrate that GCC19CART has an acceptable safety profile and meaningful clinical activity in refractory metastatic colorectal cancer. This trial is ongoing and updated data will be presented, including from patients treated at dose level 2 (2x10 6 CAR-T cells/kg). Clinical trial information: NCT05319314 .