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Non-Secreted Mature Decoy-Resistant IL-18-Armed Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in an Aggressive Murine Ovarian Cancer Model
Journal article   Open access   Peer reviewed

Non-Secreted Mature Decoy-Resistant IL-18-Armed Oncolytic Vaccinia Virus Elicits Potent Antitumor Effects in an Aggressive Murine Ovarian Cancer Model

Pingpo Ming, Chunyan Li, Junjie Ye, Lingjuan Chen, Julia Waltermire, Jinshun Zhao, Maya Eid, Ting Zhang, Wei Ge, Jinghua Ren, …
Cancers, v 18(7), 1065
25 Mar 2026
DOI: https://doi.org/10.3390/cancers18071065
PMID: 41976287
url
https://doi.org/10.3390/cancers18071065View
Published, Version of Record (VoR) Open CC BY V4.0

Abstract

Ovarian cancer is often diagnosed at advanced stages and frequently leads to the buildup of fluid in the abdomen, called ascites, which causes discomfort and weakens the body’s ability to fight the tumor. New treatment strategies are needed to improve outcomes for patients with advanced disease. In this study, we tested a modified virus designed to selectively infect tumors and stimulate the immune system. The virus was engineered to produce a form of the immune-activating protein interleukin-18 that helps boost immune responses. In a mouse model of aggressive ovarian cancer, treatment with this engineered virus improved survival and reduced abdominal swelling associated with fluid accumulation. The therapy was also linked to increased activation of immune cells that can recognize and attack tumors. These findings suggest that this virus-based approach may help strengthen antitumor immunity and could be further developed as a potential treatment strategy for ovarian cancer. Background/Objectives: Ovarian cancer is the most lethal gynecologic malignancy, largely due to late diagnosis and the high prevalence of malignant ascites, a hallmark of advanced disease that is difficult to control and contributes to immune suppression and treatment failure. Despite advances in standard care, durable responses are rare. This study investigates a novel immunotherapeutic strategy designed to overcome the suppressed peritoneal microenvironment using an oncolytic vaccinia virus engineered to express a decoy-resistant IL-18 mutein. Methods: We generated a vaccinia virus (vvDD-nsmDR-18) expressing a non-secreted, mature, decoy-resistant IL-18. Viral expression was validated via RT-qPCR and fluorescence microscopy, while cytotoxicity was confirmed using CCK-8 assays. The antitumor efficacy of vvDD-nsmDR-18 was evaluated in the aggressive murine ID8a ovarian cancer model. The underlying mechanisms of action were investigated using flow cytometry and transcriptional profiling. Results: Treatment with vvDD-nsmDR-18 significantly prolonged survival and was associated with reduced abdominal distension consistent with decreased ascites burden. Immune analyses indicated enhanced T cell activation across multiple anatomical compartments, including tumors, peritoneal cavity, and spleens, the latter recently suggested to serve as a reservoir for tumor-reactive T cells. This systemic activation was characterized by increased IFN-γ and perforin expression. In addition, vvDD-nsmDR-18 treatment was associated with expansion of CD39+CD103+CD8+ tumor-reactive T cells and a shift toward a lower PD-1 expression phenotype within this population. Conclusions: These findings demonstrate that nsmDR-18-expressing oncolytic viruses can remodel the immunosuppressive landscape of advanced ovarian cancer, suggesting this approach is a promising candidate for further clinical development.

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