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用于癌症免疫治疗的T细胞衔接器的创新策略。

Innovative strategies for T cell engagers for cancer immunotherapy.

作者信息

Bergamaschi Cristina, Gaspar Miguel, Ciucci Thomas, Sitnikova Suzanne I, Cayatte Corinne, Pica Mike, Dovedi Simon J

机构信息

Oncology R&D, AstraZeneca, Gaithersburg, MD, USA.

Oncology R&D, AstraZeneca, Cambridge, UK.

出版信息

MAbs. 2025 Dec;17(1):2531223. doi: 10.1080/19420862.2025.2531223. Epub 2025 Jul 10.


DOI:10.1080/19420862.2025.2531223
PMID:40641219
Abstract

T cell engagers (TCEs) are a promising class of cancer immunotherapy that re-direct T cells to kill tumor cells. However, their clinical application is limited by several challenges, including cytokine release syndrome (CRS), on-target off-tumor toxicity and overcoming immunosuppression in both hematological and solid tumors. This review explores recent innovations in TCE design aimed at improving their safety and efficacy. Key developments include optimizing geometry to facilitate effective immune synapses, affinity optimization of the anti-CD3/TCR domain and targeting of specific T cell subsets which both aim to reduce CRS. Logic-gated approaches such as dual-targeted and conditional TCEs activated by tumor microenvironment factors have the potential to reduce on target, off tumor toxicity and potentially increase the depth and durability of response. Additionally, leveraging costimulatory signaling offers the potential to further improve efficacy across hematological and solid tumor settings. The next generation of TCEs is expected to overcome some of the limitations of conventional TCEs, enhancing their therapeutic window and enabling combination therapies. As the field advances, TCEs are poised to become a cornerstone of cancer immunotherapy, potentially improving outcomes for a broader range of patients than the ones currently benefiting from conventional immunotherapy.

摘要

T细胞衔接器(TCEs)是一类很有前景的癌症免疫疗法,可重新引导T细胞杀死肿瘤细胞。然而,它们的临床应用受到若干挑战的限制,包括细胞因子释放综合征(CRS)、靶上脱瘤毒性以及克服血液系统肿瘤和实体瘤中的免疫抑制。本综述探讨了TCE设计方面的最新创新,旨在提高其安全性和疗效。关键进展包括优化几何结构以促进有效的免疫突触形成、抗CD3/TCR结构域的亲和力优化以及特定T细胞亚群的靶向,这些都旨在减少CRS。逻辑门控方法,如由肿瘤微环境因素激活的双靶向和条件性TCEs,有可能降低靶上脱瘤毒性,并有可能增加反应的深度和持久性。此外,利用共刺激信号有可能在血液系统肿瘤和实体瘤环境中进一步提高疗效。预计下一代TCEs将克服传统TCEs的一些局限性,扩大其治疗窗口并实现联合疗法。随着该领域的发展,TCEs有望成为癌症免疫疗法的基石,可能为比目前从传统免疫疗法中受益的患者范围更广的患者改善治疗结果。

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引用本文的文献

[1]
Unconventional Immunotherapies in Cancer: Opportunities and Challenges.

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本文引用的文献

[1]
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Proc Natl Acad Sci U S A. 2025-6-3

[2]
Tri-specific tribodies targeting 5T4, CD3, and immune checkpoint drive stronger functional T-cell responses than combinations of antibody therapeutics.

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[3]
SAIL66, a next generation CLDN6-targeting T-cell engager, demonstrates potent antitumor efficacy through dual binding to CD3/CD137.

J Immunother Cancer. 2024-10-14

[4]
ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells.

Nat Cancer. 2024-10

[5]
IL-2-armored peptide-major histocompatibility class I bispecific antibodies redirect antiviral effector memory CD8+ T cells to induce potent anti-cancer cytotoxic activity with limited cytokine release.

MAbs. 2024

[6]
IL-2 based cancer immunotherapies: an evolving paradigm.

Front Immunol. 2024-7-24

[7]
Linvoseltamab for Treatment of Relapsed/Refractory Multiple Myeloma.

J Clin Oncol. 2024-8-1

[8]
IL2 Targeted to CD8+ T Cells Promotes Robust Effector T-cell Responses and Potent Antitumor Immunity.

Cancer Discov. 2024-7-1

[9]
Engineering CD3/CD137 Dual Specificity into a DLL3-Targeted T-Cell Engager Enhances T-Cell Infiltration and Efficacy against Small-Cell Lung Cancer.

Cancer Immunol Res. 2024-6-4

[10]
Geometric Antibody Engineering Reveals the Spatial Factor on the Efficacy of Bispecific T Cell Engagers.

ACS Chem Biol. 2024-4-19

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