双特异性抗体免疫疗法在胶质母细胞瘤治疗中的研究进展
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1.山东第二医科大学临床医学院;2.烟台毓璜顶医院(青岛大学附属烟台毓璜顶医院)

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Research Progress on Bispecific Antibody Immunotherapy in the Treatment of Glioblastoma
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1.山东第二医科大学临床医学院;2.School of Clinical Medicine, Shandong Second Medical University;3.Neurosurgery Department of Yantai Yuhuangding Hospital

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    摘要:

    胶质母细胞瘤(GBM)的治疗因免疫抑制微环境、血脑屏障(BBB)阻隔及高度异质性而面临严峻挑战,对免疫检查点抑制剂(ICIs)等传统疗法反应不佳。双特异性抗体(BsAbs)通过同时桥接T细胞与肿瘤抗原(如EGFRvIII、HER2、B7-H3),在临床前研究中展现出克服GBM治疗困境的潜力。本综述系统分析了BsAbs(包括双特异性T细胞衔接器BiTE)在GBM治疗中的研究进展与作用机制。研究表明,靶向上述抗原的BsAbs能有效激活T细胞、促进其肿瘤浸润并特异性杀伤GBM细胞,显著提高多种临床前模型(如原位异种移植模型、人源化模型)的生存率(例如,部分模型生存期显著延长,P<0.0001)。BiTE疗法在诱导持久抗肿瘤效应方面亦显示出前景。然而,BsAbs在GBM应用中仍需解决关键瓶颈,包括BBB穿透效率、潜在的脱靶毒性及免疫原性。此外,本综述探讨了优化BsAbs(如通过亲和力与构型工程提升特异性)及联合策略(如联用ICIs、放疗或纳米递送系统)以增强疗效和安全性的最新进展。随着抗体工程技术的进步,优化设计的BsAbs有望成为改善GBM患者预后的有效治疗工具。

    Abstract:

    The treatment of glioblastoma (GBM) faces significant challenges due to the immunosuppressive microenvironment, the blood-brain barrier (BBB), and high heterogeneity, resulting in poor responses to conventional therapies such as immune checkpoint inhibitors (ICIs). Bispecific antibodies (BsAbs), which can simultaneously bridge T cells and tumor antigens (such as EGFRvIII, HER2, B7-H3), have demonstrated potential in overcoming the therapeutic challenges of GBM in preclinical studies. This review systematically analyzes the research progress and mechanisms of action of BsAbs, including bispecific T-cell engagers (BiTEs), in the treatment of GBM. Studies have shown that BsAbs targeting the aforementioned antigens can effectively activate T cells, promote their tumor infiltration, and specifically kill GBM cells, significantly improving survival rates in various preclinical models (such as orthotopic xenograft models and humanized models), with some models showing a significant extension of survival time (P<0.0001). BiTE therapy also shows promise in inducing durable antitumor effects. However, there are still critical bottlenecks to address in the application of BsAbs in GBM, including BBB penetration efficiency, potential off-target toxicity, and immunogenicity. Additionally, this review explores the latest advances in optimizing BsAbs, such as enhancing specificity through affinity and configuration engineering, and combination strategies like co-administration with ICIs, radiotherapy, or nanodelivery systems to improve efficacy and safety. With advancements in antibody engineering technology, optimally designed BsAbs are expected to become effective therapeutic tools for improving the prognosis of GBM patients.

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  • 收稿日期:2024-10-15
  • 最后修改日期:2025-06-25
  • 录用日期:2025-01-06
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