Vercher Enric, Covo-Vergara Ángela, Conde Enrique, Hernández-Rueda Mercedes, Elizalde Edurne, Mancheño Uxua, Glez-Vaz Javier, Tamayo-Uria Ibon, García-García Maritza R, Ferrer-Roig Marta, Marañón-Lopez Javier, Repáraz David, Ruiz Marta, López-Díaz de Cerio Ascensión, Inogés Susana, Iñarrairaegui Mercedes, Lasarte Juan J, Sangro Bruno, Sarobe Pablo, Hervas-Stubbs Sandra
Immunology and Immunotherapy Program,Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Hepatology. 2024 Nov 26. doi: 10.1097/HEP.0000000000001175.
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.
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.
Transgenic TCRs join forces with CARs, expanding the arsenal of GPC3-targeting receptors for HCC T-cell therapy.
磷脂酰肌醇蛋白聚糖-3（GPC3）是肝癌T细胞治疗中一个很有前景的靶点。虽然靶向GPC3的嵌合抗原受体（CAR）T细胞已显示出治疗效果，但其有效性受到诸如持久性低和表面GPC3脱落等挑战的限制。天然T细胞受体（TCR）可能是一种替代方案，不过在内源库中鉴定GPC3特异性TCR很困难。
我们用表达人GPC3的腺病毒免疫人白细胞抗原A2（HLA-A2）转基因小鼠，鉴定出一组识别GPC3(522 - 530)表位的TCR。我们克隆了3种鼠源GPC3-TCR（TCR-A、TCR-B和TCR-C），并构建了原代人T细胞（TCR-T）。TCR-T细胞能有效识别GPC3 + HLA-A2 + 人肝癌细胞，GPC3沉默和HLA-A2阻断会降低识别能力。TCR-B-T和TCR-C-T细胞表现出最高的反应性，其中TCR-B-T细胞在异种移植肝癌模型中表现出卓越的效应器功能、增殖能力和治疗效果显著。值得注意的是，TCR-B-T细胞优于第二代41BB GPC3特异性CAR-T细胞，这归因于更低的耗竭、更强的增殖、更大的效应器功能和更好的恢复力。此外，CAR-T和TCR-B-T细胞混合给药比相同细胞类型的交错给药显著更有效，表明可能存在协同效应。
转基因TCR与CAR联合，扩大了肝癌T细胞治疗中靶向GPC3受体的武器库。
