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

Year: 2025

Type: article

Abstract: 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. 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 8 , 3×10 8 , and 10×10 8 cells. The endpoints included dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetic parameters, and anti-tumor activity. Exploratory endpoints were predefined to evaluate potential biomarkers. Six patients received an infusion of JWATM204, with two patients in each dose group. Only two cases of cytokine release syndrome (CRS) were reported, both mild to moderate (Grade 2 and Grade 1, respectively), and both 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 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%), resulting in 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 CRP and CYP2E1 expression in PD patients, which declined after therapy, suggesting potential links between inflammation and treatment response. 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 CRP and CYP2E1 may serve as potential biomarkers for treatment response, providing a basis for further optimization of CAR T cell therapy in HCC. https://clinicaltrials.gov/ ; ID: NCT06144385 • JWATM204 showed favorable safety in refractory patients with poor prognosis. • Preliminary efficacy was observed in advanced hepatocellular carcinoma (HCC) with varying Glypican-3 (GPC3) expression. • Promising disease control was observed in high-tumor-burden advanced HCC. • Peripheral blood natural killer (NK) cell proportion and tissue C-reactive protein/ Cytochrome P450 family 2 subfamily E member ( CRP / CYP2E1) expression levels may predict response to chimeric antigen receptor (CAR) T cell therapy.

Source: Cancer Pathogenesis and Therapy

DOI: 10.1016/j.cpt.2025.12.002