肿瘤细胞治疗研究
英文原题：Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density.
Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density.
嵌合抗原受体（CAR）T 细胞在血液肿瘤中显示出前景，但在实体瘤中面临挑战，部分原因在于抗原密度的异质性。
嵌合抗原受体（CAR）T细胞在血液系统恶性肿瘤中显示出良好前景，但在实体瘤中仍面临挑战，部分原因是抗原密度不均一。GPC2是一种癌胚抗原，在神经母细胞瘤中高表达，目前正在I期临床试验中评估。本研究构建了靶向GPC2的抗体-T细胞受体（AbTCR）工程化T细胞。研究使用CT3或人源化CT3（hCT3）抗原结合片段（Fab），将其与γ/δ T细胞受体（TCR）连接，并加入CD30共刺激结构域，制备自体AbTCR T细胞。与CT3 CAR-T相比，CT3和hCT3 AbTCR T细胞均表现出更强的抗肿瘤疗效；其中hCT3 AbTCR T细胞可使GPC2抗原密度较低的神经母细胞瘤显著消退。疗效增强与更强的TCR信号、干细胞样记忆T细胞扩增及CD8+ T细胞浸润增加相关。研究结果凸显hCT3 AbTCR T细胞治疗神经母细胞瘤的潜力，并提示AbTCR T细胞可能广泛用于实体瘤。
Chimeric antigen receptor (CAR) T cells have shown promise in hematological cancers but face challenges in solid tumors, partly due to heterogeneous antigen density. Glypican-2 (GPC2) is an oncofetal antigen highly expressed in neuroblastoma and under evaluation in phase 1 clinical trials. Here, we engineer T cells with antibody-T cell receptors (AbTCRs) targeting GPC2. We generate autologous AbTCR T cells using CT3 or humanized CT3 (hCT3) antigen-binding fragments (Fab) linked to / T cell receptors (TCRs), along with a CD30 co-stimulatory domain. Both CT3 and hCT3 AbTCR T cells show superior antitumor efficacy compared to CT3 CAR T cells, with hCT3 AbTCR T cells inducing significant regression in neuroblastoma with low GPC2 antigen density. Enhanced efficacy is associated with stronger TCR signaling, expansion of stem cell-like memory T cells, and improved CD8 + T cell infiltration. These results highlight the potential of hCT3 AbTCR T cells for neuroblastoma and indicate broad application of AbTCR T cells in solid tumors.
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