Enhanced Functionality of Anti-GPC3 CAR-T Cells Against Hepatocellular Carcinoma Through Locoregional Administration

Area of Science:

• Immunotherapy
• Oncology
• Hepatocellular Carcinoma Research

Background:

• Hepatocellular carcinoma (HCC) prognosis remains poor despite immunotherapy advancements.
• Chimeric antigen receptor (CAR) T cell therapy targeting glypican-3 (GPC3) shows promise for HCC but faces challenges with patient response and CAR-T cell infiltration.
• Locoregional administration is a potential strategy for solid tumor CAR-T therapy, but its application in HCC requires further investigation.

Purpose of the Study:

• To evaluate the therapeutic efficacy of locoregional versus systemic administration of anti-GPC3 CAR-T cells in HCC.
• To investigate the impact of portal vein injection on CAR-T cell infiltration, function, and anti-tumor activity in HCC models.

Main Methods:

• Construction of anti-GPC3 CAR-T cells.
• Assessment of therapeutic efficacy using locoregional (portal vein) and systemic (tail vein) administration in multiple HCC xenograft mouse models.
• Evaluation of CAR-T cell infiltration, cytotoxicity, chemotaxis, exhaustion, and liver function.

Main Results:

• Locoregional CAR-T therapy via portal vein injection significantly enhanced tumor growth inhibition compared to tail vein injection in orthotopic HCC models.
• Portal vein injection led to increased CAR-T cell infiltration, improved cytotoxicity, enhanced chemotaxis, and reduced exhaustion.
• Escalating CAR-T cell dosages improved CAR-T cell functionality and treatment efficacy, with improved liver function observed.
• Portal vein injection demonstrated superior tumor inhibition in a metastatic HCC model.

Conclusions:

• Locoregional CAR-T therapy through the portal vein increases CAR-T cell infiltration and therapeutic efficacy in HCC.
• This approach holds promise for treating both early- and late-stage hepatocellular carcinoma patients.