GCC19CART, a novel CAR T-cell therapy, has shown promising clinical antitumor activity in patients with refractory metastatic colorectal cancer (mCRC). Preliminary findings from an ongoing phase 1 trial (NCT05319314), presented at the 2025 Gastrointestinal Cancers Symposium, indicate that the therapy could offer a new treatment option for patients with limited alternatives. The study, led by Bridget Keenan, MD, PhD, of UCSF Helen Diller Family Comprehensive Cancer Center, provides early evidence of the potential of GCC19CART in a challenging patient population.
The phase 1 dose-escalation study evaluated the safety and efficacy of GCC19CART in patients with mCRC that was refractory to standard chemotherapy. Patients underwent leukapheresis followed by lymphodepleting chemotherapy with fludarabine and cyclophosphamide. They then received a single infusion of GCC19CART at one of two dose levels: 1 x 10⁶ cells/kg (dose level 1) or 2 x 10⁶ cells/kg (dose level 2).
Efficacy Outcomes
At dose level 1 (n = 4), the overall response rate (ORR) was 25.0%, with one patient achieving a confirmed partial response (PR) and two others showing partial metabolic responses with stable disease (SD). Dose level 2 (n = 5) yielded a higher ORR of 80.0%, including one patient with a pathological complete response and three with PR. The fifth patient at this level had a complete metabolic response on PET/CT. Across both dose levels (n = 9), the ORR was 56%, and the disease control rate was 78%.
The median progression-free survival (PFS) was 5.0 months in dose level 1 and 7.8 months in dose level 2, with median follow-ups of 16.6 months and 7.4 months, respectively. These results suggest a potential for durable disease control in some patients.
Safety Profile
Cytokine release syndrome (CRS) was observed in all patients, with the majority experiencing grade 1 (66.7%) or grade 2 (33.3%) CRS. Immune effector cell–associated neurotoxicity syndrome (ICANS) occurred in two patients, one at grade 2 (11.1%) and one at grade 3 (11.1%). Diarrhea was a common adverse event, reported in 8 of 9 patients, with varying grades of severity.
One patient treated at dose level 2 experienced a dose-limiting toxicity, including grade 3 diarrhea, grade 4 enterocolitis, and grade 5 sepsis, ultimately leading to death due to fungal sepsis 48 days post-infusion. According to Keenen, adverse effects were related to the GCC19CART mechanism and were consistent with what has been observed with other CAR T-cell products. Strategies to further optimize the management of treatment-related diarrhea and colitis are currently being implemented.
Study Design and Patient Characteristics
GCC19CART is the first clinical candidate from the CoupledCAR solid tumor platform, designed to enhance proliferation, activation, and persistence against solid tumors by pairing solid tumor CAR T cells with CD19-targeting CAR T cells. The therapy targets GCC, a known mucosal marker.
Initially, patients were screened for GCC expression, but this practice was discontinued after it was found that 95% of screened patients with mCRC were GCC positive. The primary endpoint of the trial was safety, with secondary endpoints including ORR, duration of response, PFS, overall survival, and pharmacokinetics.
The median age of the nine patients was 48 years (range, 39-57). Most patients were male (56%) and had received a median of three prior lines of therapy (range, 2-5). The disease originated primarily from the left colon (44%) and rectum (44%).
