小细胞肺癌中DLL3靶向治疗的演变格局。
完整摘要 · 中文译文
小细胞肺癌（SCLC）仍然是最致命的胸部恶性肿瘤之一，其特征是进展迅速、早期转移以及对常规治疗的持久反应有限。Delta样配体3（DLL3）是一种Notch通路抑制性配体，在大约70-85%的SCLC肿瘤细胞表面异常过表达，但在正常成人组织中基本不表达，已成为一个引人注目且可靶向治疗的靶点。早期通过抗体药物偶联物（ADC）rovalpituzumab tesirine（Rova-T）利用DLL3的努力，尽管在III期试验中未能显示出生存获益，但产生了重要的机制性见解，并推动了一代更精细的靶向DLL3策略的诞生。本综述批判性地审视了不断发展的DLL3靶向治疗策略组合，涵盖三种主要模式：T细胞衔接器、ADC和嵌合抗原受体T细胞（CAR-T）疗法。同时，我们审视了正在重塑更广泛SCLC格局的新兴非DLL3治疗策略。我们还讨论了支撑DLL3作为生物标志物的转化科学，包括基于循环肿瘤细胞的液体活检和DLL3靶向免疫PET-CT成像在患者选择和治疗监测中的新兴作用。
完整摘要 · 英文原文
Small cell lung cancer (SCLC) remains one of the most lethal thoracic malignancies, characterized by rapid progression, early metastasis, and limited durable responses to conventional therapy. Delta-like ligand 3 (DLL3), a Notch pathway inhibitory ligand aberrantly overexpressed on the surface of approximately 70-85% of SCLC tumor cells but largely absent from normal adult tissue, has emerged as a compelling and therapeutically actionable target. Early efforts to exploit DLL3 through the antibody-drug conjugate (ADC) rovalpituzumab tesirine (Rova-T) yielded important mechanistic insights despite failing to demonstrate survival benefit in phase III trials and have since catalyzed a new generation of more refined DLL3-directed strategies. This review critically examines the evolving portfolio of DLL3-targeted therapies across three principal modalities: T-cell engagers, ADCs, and chimeric antigen receptor T-cell (CAR-T) therapies. In parallel, we examine emerging non-DLL3 therapeutic strategies reshaping the broader SCLC landscape. We additionally discuss the translational science underpinning DLL3 as a biomarker, including the emerging roles of circulating tumor cell-based liquid biopsy and DLL3-directed immunoPET-CT imaging in patient selection and treatment monitoring.