Safety and efficacy of JWATM204, a novel Glypican-3 (GPC3)-targeted CAR T cell therapy for advanced hepatocellular carcinoma: A phase I dose-escalation study.

Background: Glypican-3 (GPC3) is an important therapeutic target for chimeric antigen receptor (CAR) T cell therapy in hepatocellular carcinoma (HCC). JWATM204 is a novel GPC3-targeted CAR T cell therapy developed on the Antibody Redirected T Cells with Endogenous Modular Immune Signaling (ARTEMIS) T-cell platform, combining the high affinity and specificity of an anti-GPC3 monoclonal antibody with enhanced safety profiles. This Phase I study aimed to evaluate the safety and tolerability of JWATM204 in patients with advanced HCC. Methods: This single-arm, single-center, open-label Phase I dose-escalation study enrolled patients with GPC3-positive advanced HCC refractory to prior anti-tumor therapy. Three doses of JWATM204 were used: 1 × 10 Results: Six patients received an infusion of JWATM204, with two patients in each dose group. Only two instances of cytokine release syndrome (CRS) were observed, both were mild to moderate (Grade 2 and Grade 1, respectively), and resolved rapidly with standard management, demonstrating a favorable safety profile. No predefined DLTs were observed, and no cases of neurotoxicity or other serious treatment-related AEs occurred. Further dose escalation was not pursued due to strategic adjustments by collaborative partners and patient accrual challenges during the coronavirus disease 2019 (COVID-19) pandemic. Two patients achieved stable disease (SD; 33.3%; 95% confidence interval [CI], 5.9-70.0), while four experienced progressive disease (PD; 66.7%; 95% CI, 30.0%-94.1%), which yielded a disease control rate of 33.3% (95% CI, 5.9%-70.0%). As of the data cutoff date, one patient remained alive; three deaths were attributed to PD, one to COVID-19 co-infection, and one to intracranial hemorrhage. The median follow-up duration was 5.05 months (range, 3.00-25.90 months), with a median progression-free survival of 3.12 months (range, 2.07-5.77 months) and a median overall survival (OS) of 5.05 months (range, 3.00-25.90 months). The 6-month and 1-year OS rates were both 33.3% (95% CI, 5.9%-70.0%). Peripheral blood immune profiling suggested that patients with SD had higher proportions of natural killer (NK) cells both before and after treatment. RNA sequencing of pre-treatment tumor samples showed upregulated Conclusions: JWATM204 demonstrated a favorable safety profile and showed preliminary anti-tumor activity in patients with advanced GPC3-positive HCC. Peripheral blood NK cell levels and tumor expression of Trial registration: https://clinicaltrials.gov/; ID: NCT06144385.