Valenzuela-Cardenas Miriam, Fisher Carrie, Bartee Mee Y, Bartee Eric
Department of Internal Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA.
Mol Ther Oncol. 2024 Aug 27;32(3):200866. doi: 10.1016/j.omton.2024.200866. eCollection 2024 Sep 19.
Cytokine therapy represents an attractive option to improve the outcomes of cancer patients. However, the systemic delivery of these agents often leads to severe immune-related toxicities, which can prevent their efficient clinical use. One approach to address this issue is the use of recombinant oncolytic viruses to deliver various cytokines directly to the tumor. This improves the biodistribution of the secreted cytokine-transgenes, both augmenting antitumor immune responses and decreasing systemic toxicities. We have shown recently that a doubly recombinant oncolytic myxoma virus that secretes a soluble version of PD1 as well as an interleukin-12 (IL-12) fusion protein (vPD1/IL-12) can cause potent regression of disseminated cancers. Here we show that, despite the predominant localization of both transgenes within the infected tumor, treatment with vPD1/IL-12 still results in systemic, IL-12-mediated toxicities. Interestingly, these toxicities are independent of interferon-γ and instead appear to be mediated by the interaction of tumor necrosis factor α with tumor necrosis factor receptor 2 on hematopoietic cells. Critically, this unique mechanism allows for vPD1/IL-12-mediated toxicities to be alleviated through the use of US Food and Drug Administration (FDA)-approved tumor necrosis factor (TNF) blockers such as etanercept.
细胞因子疗法是改善癌症患者治疗效果的一个有吸引力的选择。然而，这些药物的全身递送往往会导致严重的免疫相关毒性，这可能会阻碍它们在临床上的有效应用。解决这一问题的一种方法是使用重组溶瘤病毒将各种细胞因子直接递送至肿瘤。这改善了分泌的细胞因子转基因的生物分布，既能增强抗肿瘤免疫反应，又能降低全身毒性。我们最近发现，一种双重组溶瘤黏液瘤病毒，它分泌可溶性PD1以及白细胞介素-12（IL-12）融合蛋白（vPD1/IL-12），可导致播散性癌症显著消退。在此我们表明，尽管两个转基因主要定位于受感染的肿瘤内，但用vPD1/IL-12治疗仍会导致全身性的、IL-12介导的毒性。有趣的是，这些毒性与干扰素-γ无关，而是似乎由肿瘤坏死因子α与造血细胞上的肿瘤坏死因子受体2相互作用介导。至关重要的是，这种独特的机制使得通过使用美国食品药品监督管理局（FDA）批准的肿瘤坏死因子（TNF）阻滞剂（如依那西普）可以减轻vPD1/IL-12介导的毒性。
