Department of Internal Medicine, Rush University Medical Center, Chicago, IL, 60612, USA.
Department of Surgery, Rush University Medical Center, Chicago, IL, 60612, USA.
J Transl Med. 2023 Jul 19;21(1):483. doi: 10.1186/s12967-023-04344-8.
Viral therapies developed for cancer treatment have classically prioritized direct oncolytic effects over their immune activating properties. However, recent clinical insights have challenged this longstanding prioritization and have shifted the focus to more immune-based mechanisms. Through the potential utilization of novel, inherently immune-stimulating, oncotropic viruses there is a therapeutic opportunity to improve anti-tumor outcomes through virus-mediated immune activation. PV001-DV is an attenuated strain of Dengue virus (DEN-1 #45AZ5) with a favorable clinical safety profile that also maintains the potent immune stimulatory properties characterstic of Dengue virus infection.
In this study, we utilized in vitro tumor killing and immune multiplex assays to examine the anti-tumor effects of PV001-DV as a potential novel cancer immunotherapy.
In vitro assays demonstrated that PV001-DV possesses the ability to directly kill human melanoma cells lines as well as patient melanoma tissue ex vivo. Importantly, further work demonstrated that, when patient peripheral blood mononuclear cells (PBMCs) were exposed to PV001-DV, a substantial induction in the production of apoptotic factors and immunostimulatory cytokines was detected. When tumor cells were cultured with the resulting soluble mediators from these PBMCs, rapid cell death of melanoma and breast cancer cell lines was observed. These soluble mediators also increased dengue virus binding ligands and immune checkpoint receptor, PD-L1 expression.
The direct in vitro tumor-killing and immune-mediated tumor cytotoxicity facilitated by PV001-DV contributes support of its upcoming clinical evaluation in patients with advanced melanoma who have failed prior therapy.
为癌症治疗而开发的病毒疗法经典地优先考虑直接溶瘤作用，而不是其免疫激活特性。然而，最近的临床见解挑战了这种长期的优先次序，并将重点转移到更多基于免疫的机制上。通过利用新型、固有免疫刺激的肿瘤病毒，有可能通过病毒介导的免疫激活来改善抗肿瘤疗效。PV001-DV 是一种减毒的登革热病毒（DEN-1#45AZ5）株，具有良好的临床安全性，同时保持登革热病毒感染的强效免疫刺激特性。
在这项研究中，我们利用体外肿瘤杀伤和免疫多重分析来研究 PV001-DV 作为一种潜在的新型癌症免疫疗法的抗肿瘤作用。
体外实验表明，PV001-DV 具有直接杀伤人类黑色素瘤细胞系以及患者黑色素瘤组织的能力。重要的是，进一步的工作表明，当患者外周血单核细胞（PBMCs）暴露于 PV001-DV 时，检测到凋亡因子和免疫刺激细胞因子的大量诱导。当肿瘤细胞与这些 PBMC 产生的可溶性介质共培养时，观察到黑色素瘤和乳腺癌细胞系的快速细胞死亡。这些可溶性介质还增加了登革热病毒结合配体和免疫检查点受体 PD-L1 的表达。
PV001-DV 介导的直接体外肿瘤杀伤和免疫介导的肿瘤细胞毒性为其即将在先前治疗失败的晚期黑色素瘤患者中的临床评估提供了支持。
