GPC3-specific dnTGFβRII-armoured CAR T cells for hepatocellular carcinoma

Area of Science:

• Immunotherapy
• Oncology
• Biotechnology

Background:

• Hepatocellular carcinoma (HCC) expresses Glypican-3 (GPC3), a target for CAR T cell therapy.
• Previous GPC3-targeted CAR T cell therapy showed limited efficacy due to tumor microenvironment factors like TGFβ.
• Engineered CAR T cells with a dominant-negative TGFβ receptor II (C-CAR031) were developed to overcome resistance.

Purpose of the Study:

• To evaluate the safety and efficacy of C-CAR031 in patients with advanced, treatment-refractory HCC.
• To assess tumor response, survival outcomes, and adverse events associated with C-CAR031 therapy.

Main Methods:

• A first-in-human Phase I trial (NCT05155189) involving 36 patients with advanced HCC.
• Patients received C-CAR031 CAR T cell infusions at escalating dose levels.
• Tumor samples were analyzed using high-throughput methods to identify resistance mechanisms.

Main Results:

• Tumor regression was observed in 32 patients, with a median best reduction of 41.6%.
• Objective response rate was 44.4%, with median progression-free survival of 4.2 months and overall survival of 14.2 months.
• Cytokine release syndrome occurred in 34 patients; two were grade 3. Nine patients experienced grade 3+ non-hematological adverse events.

Conclusions:

• C-CAR031 demonstrates a manageable safety profile and encouraging anti-tumor activity in heavily pretreated advanced HCC patients.
• GPC3 antigen loss and increased TGFβ levels were identified as potential mechanisms of resistance.
• This engineered CAR T cell therapy represents a promising approach for advanced HCC, warranting further investigation.