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

175 Background: GCC19CART, the first clinical candidate from the CoupledCAR solid tumor platform, pairs solid tumor CAR T-cells with CD19-targeting CAR T-cells to enhance proliferation, activation, and persistence against solid tumors. GCC19CART targets guanylate cyclase-C (GCC), a known mucosal marker. Building on the promising results from a clinical trial in China, a phase 1 study was initiated in the US for patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapy. As of August 14, 2024, a total of 9 subjects have been treated. Methods: Subjects were initially screened for GCC expression, however screening was discontinued after >95% of subjects with mCRC demonstrated GCC expression by immunohistochemistry (95/98). Eligible subjects underwent leukapheresis, lymphodepleting chemotherapy (fludarabine 30mg/m 2 and cyclophosphamide 300mg/m 2 on day-3), and then infusion of a single dose GCC19CART. Objective response was assessed by RECIST v1.1. Results: Four subjects have been enrolled at dose level 1 (1x10 6 cells/kg) and 5 subjects at dose level 2 (2x10 6 cells/kg). The most common adverse events were cytokine release syndrome (CRS) in 9/9 subjects (Grade 1: 6/9 [66.7%] and Grade 2: 3/9 [33.3%]) and diarrhea in 8/9 subjects (Grade 1: 3/9 [33.3%], Grade 2: 3/9 [33.3%], Grade 3: 2/9 [22.2%]). Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 2/9 subjects (Grade 2: 1/9 [11.1%] or Grade 3: 1/9 [11.1%]) and resolved rapidly with corticosteroid and dasatinib treatment. Three out of 9 subjects had a mild tremor (Grade 1) that resolved with corticosteroids. One subject experienced a dose-limiting toxicity (DLT) at dose level 2, presenting with Grade 3 diarrhea, Grade 4 enterocolitis and Grade 5 sepsis, and died from fungal sepsis 48 days post-infusion. At dose level 1, the overall response rate (ORR) was 50.0% (2/4). Two subjects demonstrated a partial response (PR) with one confirmed PR, while 1 additional subject had partial metabolic response on PET/CT with stable disease (SD) and 1 patient had progressive disease. At dose level 2, the ORR was 80% (4/5), including 1 subject with a pathological complete response, and 3 with a confirmed partial response, of which 1 had a complete metabolic response on PETCT. Conclusions: Preliminary results indicate that GCC19CART exhibits significant clinical activity in patients with refractory mCRC. Adverse events were related to GCC19CART mechanism and in line with what has been observed with other CAR T-cell products. Strategies to further optimize the management of treatment-related diarrhea are currently being implemented. The trial is ongoing and updated data will be presented. Clinical trial information: NCT05319314 .