<br>免疫检查点阻断与 DNA 损伤修复抑制剂组合治疗乳腺癌和卵巢癌的发展前景,Journal of Hematology & Oncology

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免疫检查点阻断与 DNA 损伤修复抑制剂组合治疗乳腺癌和卵巢癌的发展前景
Journal of Hematology & Oncology ( IF 29.5 ) Pub Date : 2021-12-20 , DOI: 10.1186/s13045-021-01218-8
Lingling Zhu ₁ , Jiewei Liu ₁ , Jiang Chen ₂ , Qinghua Zhou ₁

Affiliation

使用针对程序性死亡受体 (PD)-1、PD 配体 (PD-L)-1 和细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 的抗体进行免疫检查点阻断 (ICB) 重新定义了实体瘤的治疗前景肿瘤，包括皮肤、肺、膀胱、肝、肾和乳腺肿瘤。然而，PD-L1 阴性患者对 ICB 治疗的总体反应率仍然有限。因此，需要合理有效的联合疗法来解决这些患者以及在 ICB 治疗下病情进展的 PD-L1 阳性患者的 ICB 治疗耐药性。 DNA 损伤修复抑制剂 (DDRis) 可能会激活 T 细胞反应并触发炎症细胞因子释放，并通过放大 DNA 损伤并产生免疫原性新抗原，最终导致免疫原性癌细胞死亡，特别是在 DDR 缺陷的肿瘤中。 DDRi 还可能导致适应性 PD-L1 上调，为 PD-L1/PD-1 阻断提供理论依据。因此，基于临床前的疗效证据和无显着重叠毒性，一些 ICB/DDRi 组合已迅速进入乳腺癌和卵巢癌的临床测试阶段。在这里，我们总结了 ICB 与 DDRi 药物联合治疗乳腺癌和卵巢癌的现有临床数据，并讨论了作用机制以及迄今为止进行的转化研究中吸取的其他经验教训。我们还审查了潜在的生物标志物，以选择最有可能对 ICB/DDRi 联合治疗产生反应的患者。

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The developing landscape of combinatorial therapies of immune checkpoint blockade with DNA damage repair inhibitors for the treatment of breast and ovarian cancers

The use of immune checkpoint blockade (ICB) using antibodies against programmed death receptor (PD)-1, PD ligand (PD-L)-1, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) has redefined the therapeutic landscape in solid tumors, including skin, lung, bladder, liver, renal, and breast tumors. However, overall response rates to ICB therapy remain limited in PD-L1-negative patients. Thus, rational and effective combination therapies will be needed to address ICB treatment resistance in these patients, as well as in PD-L1-positive patients who have progressed under ICB treatment. DNA damage repair inhibitors (DDRis) may activate T-cell responses and trigger inflammatory cytokines release and eventually immunogenic cancer cell death by amplifying DNA damage and generating immunogenic neoantigens, especially in DDR-defective tumors. DDRi may also lead to adaptive PD-L1 upregulation, providing a rationale for PD-L1/PD-1 blockade. Thus, based on preclinical evidence of efficacy and no significant overlapping toxicity, some ICB/DDRi combinations have rapidly progressed to clinical testing in breast and ovarian cancers. Here, we summarize the available clinical data on the combination of ICB with DDRi agents for treating breast and ovarian cancers and discuss the mechanisms of action and other lessons learned from translational studies conducted to date. We also review potential biomarkers to select patients most likely to respond to ICB/DDRi combination therapy.

更新日期：2021-12-20

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