The efficacy of immune checkpoint blockade therapy against immunologically “cold” tumors can be enhanced by applying the checkpoint inhibitors in combination with oncolytic viruses. Alternatively, the oncolytic virus construct has been modified to express factors that boost oncolytic virus function. We engineered a novel oncolytic herpes simplex virus 2 (HSV2) encoding an anti-human programmed cell death 1 (PD-1) monoclonal antibody (oHSV2-aPD1). This virus resulted in the detectable expression of a functional monoclonal antibody against human PD-1 by infecting eukaryotic cells. Therapeutic efficacy of oHSV2-aPD1 proved superior to unmodified oncolytic HSV2 treatment or PD-1 blockade alone and as effective as their combination in the poorly immunogenic melanoma models. Additionally, local oHSV2-aPD1 treatment induced a durable antitumor response and activated many immune effector cells and molecules both in the tumor microenvironment and in the systemic immune system. This provides support for combinatorial strategies involving local administration of an oncolytic HSV2 expressing a PD-1 inhibitor.

通过将检查点抑制剂与溶瘤病毒结合使用，可以增强针对免疫学“冷”肿瘤的免疫检查点阻断疗法的疗效。备选地，溶瘤病毒构建体已被修饰以表达增强溶瘤病毒功能的因子。我们设计了一种新型的溶瘤性单纯疱疹病毒2（HSV2），编码一种抗人类程序性细胞死亡1（PD-1）单克隆抗体（oHSV2-aPD1）。该病毒通过感染真核细胞导致可检测到的针对人PD-1的功能性单克隆抗体表达。事实证明，oHSV2-aPD1的治疗效果优于未经修饰的溶瘤性HSV2治疗或单独的PD-1阻断，在免疫原性较差的黑色素瘤模型中，其疗效与它们的组合一样有效。此外，oHSV2-aPD1局部治疗可诱导持久的抗肿瘤反应，并激活肿瘤微环境和全身免疫系统中的许多免疫效应细胞和分子。这为涉及局部给药表达PD-1抑制剂的溶瘤HSV2的组合策略提供了支持。