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分泌双特异性杀伤细胞衔接器的嵌合抗原受体T细胞重定向自然杀伤细胞特异性以增强抗肿瘤反应。

Bispecific killer cell engager-secreting CAR-T cells redirect natural killer specificity to enhance antitumour responses.

作者信息

Fan Ya, Duan Yanting, Chen Jiangqing, Wang Yajie, Shang Kai, Jiang Jie, Su Lu, Zhou Chun, Sadelain Michel, Huang He, Sun Jie

机构信息

Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Liangzhu Laboratory, Zhejiang University, Hangzhou, China.

出版信息

Nat Biomed Eng. 2025 Jul 14. doi: 10.1038/s41551-025-01450-4.


DOI:10.1038/s41551-025-01450-4
PMID:40659834
Abstract

T cells and natural killer (NK) cells collaborate to maintain immune homeostasis. Current cancer immunotherapies predominantly rely on the individual application of these cells. Here we use bicistronic vectors to co-express chimeric antigen receptors (CARs) and secreted immune cell engagers (ICEs), leveraging the combined therapeutic potential of both effector cell types. After in vitro validation of immune cell engager secretion and function, various combinatorial approaches are systematically compared in mouse models, identifying a highly effective combination of bispecific killer cell engager (BiKE)-secreting CAR-T cells and NK cells. Beyond a simple combination of conventional CAR-T cells and NK cells, this strategy demonstrates superior efficacy in CD19 B cell leukaemia and lymphoma and EGFR solid tumour models while reducing the dosage dependence on CAR-T cells. Moreover, CAR-T cells and BiKEs targeting distinct antigens exhibit suppression of tumour cells with heterogeneous antigen expression. These findings indicate that combining BiKE-secreting CAR-T cells and NK cells offers a promising strategy to combat tumour antigen heterogeneity and immune evasion.

摘要

T细胞和自然杀伤(NK)细胞协同维持免疫稳态。当前的癌症免疫疗法主要依赖于这些细胞的单独应用。在此,我们使用双顺反子载体共表达嵌合抗原受体(CAR)和分泌型免疫细胞衔接器(ICE),利用这两种效应细胞类型的联合治疗潜力。在对免疫细胞衔接器的分泌和功能进行体外验证后,我们在小鼠模型中系统地比较了各种组合方法,确定了分泌双特异性杀伤细胞衔接器(BiKE)的CAR-T细胞和NK细胞的高效组合。除了传统CAR-T细胞和NK细胞的简单组合外,该策略在CD19 B细胞白血病和淋巴瘤以及EGFR实体瘤模型中显示出卓越疗效,同时降低了对CAR-T细胞的剂量依赖性。此外,靶向不同抗原的CAR-T细胞和BiKE对具有异质抗原表达的肿瘤细胞具有抑制作用。这些发现表明,联合分泌BiKE的CAR-T细胞和NK细胞为对抗肿瘤抗原异质性和免疫逃逸提供了一种有前景的策略。

相似文献

[1]
Bispecific killer cell engager-secreting CAR-T cells redirect natural killer specificity to enhance antitumour responses.

Nat Biomed Eng. 2025-7-14

[2]
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引用本文的文献

[1]
Novel cancer subtyping method guided by tumor-normal sample in latent space of transcriptomic variational autoencoder.

Sci Rep. 2025-7-21

本文引用的文献

[1]
Intraventricular CARv3-TEAM-E T Cells in Recurrent Glioblastoma.

N Engl J Med. 2024-4-11

[2]
Siglec-7 glyco-immune binding mAbs or NK cell engager biologics induce potent antitumor immunity against ovarian cancers.

Sci Adv. 2023-11-3

[3]
Long-term outcomes following CAR T cell therapy: what we know so far.

Nat Rev Clin Oncol. 2023-6

[4]
NK cells are never alone: crosstalk and communication in tumour microenvironments.

Mol Cancer. 2023-2-16

[5]
When three is not a crowd: trispecific antibodies for enhanced cancer immunotherapy.

Theranostics. 2023

[6]
Dose-response correlation for CAR-T cells: a systematic review of clinical studies.

J Immunother Cancer. 2022-12

[7]
Synthetic cytokine circuits that drive T cells into immune-excluded tumors.

Science. 2022-12-16

[8]
CAR-T cell combination therapy: the next revolution in cancer treatment.

Cancer Cell Int. 2022-11-24

[9]
Current landscape and future directions of bispecific antibodies in cancer immunotherapy.

Front Immunol. 2022

[10]
Underlying mechanisms of evasion from NK cells as rationale for improvement of NK cell-based immunotherapies.

Front Immunol. 2022

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