Antibody-gamma/delta T cell receptors targeting GPC2 regress neuroblastoma with low antigen density.

IF 10.6 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2025-09-29 DOI:10.1016/j.xcrm.2025.102378

Alex Quan, Mingyu Huo, Dan Li, Laura E Hutchins, Constanza Rodriguez, Jangsuk Oh, Hsi-En Tsao, Madeline Spetz, Elijah Edmondson, Dana Ashworth, Rui Zheng, Jing Zhou, Jinyun Chen, Jingbao Liu, Guangyan Xiong, Hongbing Zhang, Cheng Liu, Rosa Nguyen, Nan Li, Mitchell Ho

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引用次数: 0

Abstract

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 γ/δ 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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靶向GPC2的抗体- γ / δ T细胞受体治疗低抗原密度神经母细胞瘤。

嵌合抗原受体（CAR） T细胞在血液学癌症中显示出希望，但在实体肿瘤中面临挑战，部分原因是抗原密度不均。Glypican-2 （GPC2）是一种在神经母细胞瘤中高度表达的癌胎抗原，目前正处于1期临床试验评估阶段。在这里，我们设计了带有靶向GPC2的抗体T细胞受体（AbTCRs）的T细胞。我们使用CT3或人源化CT3 （hCT3）抗原结合片段（Fab）与γ/δ T细胞受体（tcr）结合，以及CD30共刺激结构域，生成了自体AbTCR T细胞。与CT3 CAR - T细胞相比，CT3和hCT3 AbTCR T细胞均显示出更好的抗肿瘤效果，hCT3 AbTCR T细胞在低GPC2抗原密度的神经母细胞瘤中诱导显著消退。增强的疗效与更强的TCR信号、干细胞样记忆T细胞的扩增和CD8+ T细胞浸润的改善有关。这些结果突出了hCT3 AbTCR T细胞治疗神经母细胞瘤的潜力，并表明AbTCR T细胞在实体肿瘤中的广泛应用。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.