DLL3 acts as an inhibitory ligand that downregulates Notch signaling and is upregulated by ASCL1, a transcription factor prevalent in the small-cell lung cancer (SCLC) subtype SCLC-A. Currently, the therapeutic strategies targeting DLL3 are varied, including antibody-drug conjugates (ADCs), bispecific T-cell engagers (BiTEs), and chimeric antigen receptor (CAR) T-cell therapies. Although rovalpituzumab tesirine (Rova-T) showed promise in a phase II study, it failed to produce favorable results in subsequent phase III trials, leading to the cessation of its development. Conversely, DLL3-targeted BiTEs have garnered significant clinical interest. Tarlatamab, for instance, demonstrated enhanced response rates and progression-free survival compared to the standard of care in a phase II trial; its biologics license application (BLA) is currently under US Food and Drug Administration (FDA) review. Numerous ongoing phase III studies aim to further evaluate tarlatamab’s clinical efficacy, alongside the development of novel DLL3-targeted T-cell engagers, both bispecific and trispecific. CAR-T cell therapies targeting DLL3 have recently emerged and are undergoing various preclinical and early-phase clinical studies. Additionally, preclinical studies have shown promising efficacy for DLL3-targeted radiotherapy, which employs β-particle-emitting therapeutic radioisotopes conjugated to DLL3-targeting antibodies. DLL3-targeted therapies hold substantial potential for SCLC management. Future clinical trials will be crucial for comparing treatment outcomes among various approaches and exploring combination therapies to improve patient survival outcomes.

中文翻译：

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DLL3引导的小细胞肺癌治疗：从抗体药物偶联物到精准免疫治疗和放射免疫治疗

DLL3 作为抑制性配体，下调 Notch 信号传导，并被 ASCL1 上调，ASCL1 是小细胞肺癌 (SCLC) 亚型 SCLC-A 中常见的转录因子。目前，针对DLL3的治疗策略多种多样，包括抗体药物偶联物（ADC）、双特异性T细胞接合剂（BiTE）和嵌合抗原受体（CAR）T细胞疗法。尽管rovalpituzumab tesirine (Rova-T)在II期研究中显示出良好的前景，但在随后的III期试验中未能产生良好的结果，导致其开发停止。相反，针对 DLL3 的 BiTE 引起了临床的广泛关注。例如，在 II 期试验中，与标准治疗相比，Tarlatamab 表现出更高的缓解率和无进展生存期；其生物制品许可申请（BLA）目前正在接受美国食品和药物管理局（FDA）的审查。许多正在进行的 III 期研究旨在进一步评估 tarlatamab 的临床疗效，同时开发新型 DLL3 靶向 T 细胞接合剂（双特异性和三特异性）。针对DLL3的CAR-T细胞疗法最近出现，并正在进行各种临床前和早期临床研究。此外，临床前研究表明，DLL3 靶向放射治疗具有良好的疗效，该疗法采用与 DLL3 靶向抗体缀合的 β 粒子发射治疗性放射性同位素。 DLL3 靶向疗法对于 SCLC 治疗具有巨大潜力。未来的临床试验对于比较各种方法的治疗结果和探索联合疗法以改善患者的生存结果至关重要。