Combinations of chemotherapy with immunotherapy have seen recent clinical success, including two approvals of anti–PD-1/L1 agents in combination with taxane-based chemotherapy in non–small cell lung cancer and triple-negative breast cancer. Here, we present a study on the combination activity and mechanistic rationale of a novel EphA2-targeted liposomal taxane (EphA2-ILs-DTXp) and anti–PD-1. This combination was highly active in mouse syngeneic tumor models, with complete responses observed in 3 of 5 models. In the EMT-6 tumor model, combination of EphA2-ILs-DTXp with anti–PD-1 resulted in a 60% complete response rate, with durable responses that were resistant to rechallenge. These responses were not observed in the absence of CD8+ T cells. Characterization of the immune infiltrates in EMT-6 tumors reveals increased CD8+ T cells, increased CD8+ IFNγ+ CTLs, and an increased CD8/regulatory T-cell (Treg) ratio. These immunomodulatory effects were not observed in mice treated with a combination of docetaxel and anti–PD-1. Pharmacokinetic analysis revealed that the AUC of docetaxel was increased 15 times, from 52.1 to 785 ng/mL/hour, when delivered by EphA2-ILs-DTXp. A dose reduction study of EphA2-ILs-DTXp showed a dose–response relationship for both tumor growth inhibition and the CD8/Treg ratio. Our data indicate that synergism between docetaxel and anti–PD-1 is achievable with nanoliposomal delivery.

中文翻译：

---

EphA2-ILs-DTXp、一种新型 EphA2 靶向纳米脂质体紫杉烷和 PD-1 抑制剂在临床前肿瘤模型中的协同作用

化学疗法与免疫疗法的结合最近取得了临床成功，包括两项批准的抗 PD-1/L1 药物联合紫杉类化学疗法治疗非小细胞肺癌和三阴性乳腺癌。在这里，我们提出了一项关于新型 EphA2 靶向脂质体紫杉烷 (EphA2-ILs-DTXp) 和抗 PD-1 的组合活性和机制原理的研究。这种组合在小鼠同基因肿瘤模型中非常活跃，在 5 个模型中的 3 个中观察到完全反应。在 EMT-6 肿瘤模型中，EphA2-ILs-DTXp 与抗 PD-1 的组合导致 60% 的完全反应率，具有对再激发具有抗性的持久反应。在不存在 CD8+ T 细胞的情况下未观察到这些反应。EMT-6 肿瘤中免疫浸润的特征表明 CD8+ T 细胞增加，CD8+ IFNγ+ CTL 增加，CD8/调节性 T 细胞 (Treg) 比率增加。在用多西紫杉醇和抗 PD-1 组合治疗的小鼠中未观察到这些免疫调节作用。药代动力学分析显示，当通过 EphA2-ILs-DTXp 给药时，多西他赛的 AUC 增加了 15 倍，从 52.1 到 785 ng/mL/小时。EphA2-ILs-DTXp 的剂量减少研究显示了肿瘤生长抑制和 CD8/Treg 比率的剂量-反应关系。我们的数据表明，多西他赛和抗 PD-1 之间的协同作用可通过纳米脂质体递送实现。1 至 785 ng/mL/小时，当由 EphA2-ILs-DTXp 提供时。EphA2-ILs-DTXp 的剂量减少研究显示了肿瘤生长抑制和 CD8/Treg 比率的剂量-反应关系。我们的数据表明，多西他赛和抗 PD-1 之间的协同作用可通过纳米脂质体递送实现。1 至 785 ng/mL/小时，当由 EphA2-ILs-DTXp 提供时。EphA2-ILs-DTXp 的剂量减少研究显示了肿瘤生长抑制和 CD8/Treg 比率的剂量-反应关系。我们的数据表明多西他赛和抗 PD-1 之间的协同作用可通过纳米脂质体递送实现。