Scientific publications
Human T cells engineered with an HLA-A2-restricted murine T-cell receptor targeting glypican 3 effectively control human hepatocellular carcinoma in mice
Enric Vercher 1 2 3, Ángela Covo-Vergara 1 2 3, Enrique Conde 1 2 3, Mercedes Hernández-Rueda 1 2 3, Edurne Elizalde 1 2 3, Uxua Mancheño 1 2 3, Javier Glez-Vaz 1 2 3, Ibon Tamayo-Uria 1 2 3, Maritza R García-García 1 2 3 4, Marta Ferrer-Roig 1 2 3, Javier Marañón-Lopez 1 2 3, David Repáraz 1 2 3, Marta Ruiz 1 2 3, Ascensión López-Díaz de Cerio 2 3 5, Susana Inogés 2 3 5, Mercedes Iñarrairaegui 2 3 6 7, Juan J Lasarte 1 2 3, Bruno Sangro 2 3 6 7, Pablo Sarobe 1 2 3 7, Sandra Hervas-Stubbs 1 2 3 7
Abstract
Background and aims: Glypican-3 (GPC3) is a promising target for T-cell therapy in HCC. While chimeric antigen receptor (CAR) T cells targeting GPC3 have demonstrated therapeutic efficacy, their effectiveness is limited by challenges such as low persistence and shedding of surface GPC3. Natural T-cell receptors (TCRs) may serve as an alternative, though identifying GPC3-specific TCRs within the endogenous repertoire is difficult.
Approach and results: We immunized human leucocyte antigen-A2 (HLA-A2) transgenic mice with an adenovirus expressing human GPC3, identifying a panel of TCRs that recognize the GPC3(522-530) epitope. We cloned 3 murine GPC3-TCRs (TCR-A, TCR-B, and TCR-C) and engineered primary human T cells (TCR-T). TCR-T cells effectively recognized GPC3 + HLA-A2 + human HCC cells, with recognition diminished by GPC3 silencing and HLA-A2 blockade. TCR-B-T and TCR-C-T cells showed the highest reactivity, with TCR-B-T cells exhibiting superior effector functions, proliferative capacity, and therapeutic efficacy in xenograft HCC models. Notable, TCR-B-T cells outperformed second-generation 41BB GPC3-specific CAR-T cells, attributed to lower exhaustion, enhanced proliferation, greater effector function, and improved resilience. Furthermore, mixed dosing of CAR-T and TCR-B-T cells was significantly more effective than staggered dosing of the same cell type, suggesting potential synergistic effects.
Conclusions: Transgenic TCRs join forces with CARs, expanding the arsenal of GPC3-targeting receptors for HCC T-cell therapy.
CITA DEL ARtÏCULO Hepatology. 2024 Nov 26. doi: 10.1097/HEP.0000000000001175. Online ahead of print.
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