Human T cells engineered with an HLA-A2-restricted murine T-cell receptor targeting glypican 3 effectively control...

Area of Science:

• Immunotherapy
• Hepatocellular Carcinoma (HCC) Research
• T-cell Receptor Engineering

Background:

• Glypican-3 (GPC3) is a key target for hepatocellular carcinoma (HCC) T-cell therapy.
• Current chimeric antigen receptor (CAR) T-cell therapies face challenges like limited persistence and GPC3 shedding.
• Identifying endogenous GPC3-specific T-cell receptors (TCRs) is difficult.

Purpose of the Study:

• To develop novel T-cell receptors (TCRs) targeting Glypican-3 (GPC3) for enhanced hepatocellular carcinoma (HCC) therapy.
• To compare the efficacy of engineered TCR T cells against existing CAR T-cell therapies.
• To explore combination strategies for improved T-cell persistence and anti-tumor activity.

Main Methods:

• Immunization of HLA-A2 transgenic mice with GPC3-expressing adenovirus to identify GPC3-specific TCRs.
• Cloning of murine GPC3-TCRs and engineering of primary human T cells (TCR-T).
• In vitro and in vivo evaluation of TCR-T cell recognition, effector functions, proliferation, and therapeutic efficacy in HCC models, including comparison with CAR-T cells.

Main Results:

• Identified and cloned three GPC3-specific TCRs (TCR-A, TCR-B, TCR-C).
• Engineered TCR-T cells effectively recognized GPC3+ HLA-A2+ HCC cells.
• TCR-B-T cells demonstrated superior effector functions, proliferation, and therapeutic efficacy in xenograft models, outperforming GPC3-specific CAR-T cells.
• Mixed dosing of CAR-T and TCR-B-T cells showed synergistic effects.

Conclusions:

• Engineered T-cell receptors (TCRs) targeting Glypican-3 (GPC3) offer a potent alternative and complementary approach to CAR T-cell therapy for HCC.
• The combination of TCRs and CARs expands therapeutic options for GPC3-positive HCC.
• TCR-B-T cells exhibit enhanced anti-tumor activity and resilience, improving upon existing CAR-T cell therapies.