用于乳腺癌的嵌合抗原受体T细胞疗法:现状与未来展望。

CAR-T cell therapy for breast cancer: Current status and future perspective.

作者信息

Buono Giuseppe, Capozzi Monica, Caputo Roberta, Lauro Vincenzo Di, Cianniello Daniela, Piezzo Michela, Cocco Stefania, Martinelli Claudia, Verrazzo Annarita, Tafuro Margherita, Calderaio Claudia, Calabrese Alessandra, Nuzzo Francesco, Pagliuca Martina, Laurentiis Michelino De

机构信息

Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy.

Istituto Nazionale Tumori, IRCCS, Fondazione G. Pascale, Napoli, Italy; Clinical and Translational Oncology, Scuola Superiore Meridionale (SSM), Napoli, Italy.

出版信息

Cancer Treat Rev. 2025 Feb;133:102868. doi: 10.1016/j.ctrv.2024.102868. Epub 2024 Dec 27.

Abstract

Within the expanding therapeutic landscape for breast cancer (BC), metastatic breast cancer (MBC) remains virtually incurable and tend to develop resistance to conventional treatments ultimately leading to metastatic progression and death. Cellular immunotherapy (CI), particularly chimeric antigen receptor-engineered T (CAR-T) cells, has emerged as a promising approach for addressing this challenge. In the wake of their striking efficacy against hematological cancers, CAR-T cells have also been used where the clinical need is greatest - in patients with aggressive BCs. Unfortunately, current outcomes fall considerably short of replicating that success, primarily owing to the scarcity of tumor-specific antigens and the immunosuppressive microenvironment within BC. Herein, we provide an up-to-date overview of both preclinical and clinical data concerning the application of CAR-T cell therapy in BC. By surveying the existing literature, we discuss the prevailing constrains of this therapeutic approach and overview possible strategies to advance it in the context of breast malignancies. Possible approaches include employing synthetic biology to refine antigen targeting and mitigate off-target toxicity, utilizing logic-gated CAR constructs to enhance specificity, and leveraging armored CARs to remodel the tumor micro-environment. Temporal and spatial regulation of CAR-T cells using inducible gene switches and external triggers further improves safety and functionality. In addition, promoting T cell homing through chemokine receptor engineering and enhancing manufacturing processes with universal CAR platforms expand therapeutic applicability. These innovations not only address antigen escape and T cell exhaustion but also optimize the efficacy and safety profile of CAR-T cell therapy. We, therefore, outline a trajectory wherein CAR-T cells may evolve from a promising experimental approach to a standard modality in BC therapy.

摘要

在乳腺癌(BC)不断拓展的治疗格局中,转移性乳腺癌(MBC)实际上仍无法治愈,并且往往会对传统治疗产生耐药性,最终导致转移进展和死亡。细胞免疫疗法(CI),特别是嵌合抗原受体工程化T(CAR-T)细胞,已成为应对这一挑战的一种有前景的方法。鉴于CAR-T细胞在治疗血液系统癌症方面取得了显著疗效,它们也被应用于临床需求最大的领域——侵袭性BC患者。不幸的是,目前的治疗效果远未达到复制那种成功,主要原因是BC中肿瘤特异性抗原的稀缺以及免疫抑制微环境。在此,我们提供了关于CAR-T细胞疗法在BC中应用的临床前和临床数据的最新概述。通过审视现有文献,我们讨论了这种治疗方法目前存在的限制,并概述了在乳腺恶性肿瘤背景下推进该疗法的可能策略。可能的方法包括利用合成生物学来优化抗原靶向并减轻脱靶毒性,使用逻辑门控CAR构建体来提高特异性,以及利用武装CAR重塑肿瘤微环境。使用可诱导基因开关和外部触发因素对CAR-T细胞进行时空调节可进一步提高安全性和功能。此外,通过趋化因子受体工程促进T细胞归巢以及利用通用CAR平台加强制造过程可扩大治疗的适用性。这些创新不仅解决了抗原逃逸和T细胞耗竭问题,还优化了CAR-T细胞疗法的疗效和安全性。因此,我们勾勒出一条轨迹,其中CAR-T细胞可能从一种有前景的实验方法演变为BC治疗的标准模式。

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