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Oncolytic vaccinia virus expressing non-secreted decoy-resistant IL-18 mutein elicits potent antitumor effects with enhanced safety
Journal article   Open access   Peer reviewed

Oncolytic vaccinia virus expressing non-secreted decoy-resistant IL-18 mutein elicits potent antitumor effects with enhanced safety

Junjie Ye, Lingjuan Chen, Sefali Patel, Pingpo Ming, Chunyan Li, Julia Waltermire, Jinshun Zhao, Jinghua Ren, David L. Bartlett and Zuqiang Liu
Molecular Therapy: Oncology, v 33(3), 201022
18 Sep 2025
DOI: https://doi.org/10.1016/j.omton.2025.201022
PMID: 40821721
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1016/j.omton.2025.201022View
Published, Version of Record (VoR) Open

Abstract

anti-CTLA-4 antibody cytokine DR-18 IL-18 immune checkpoint inhibitor MT: Regular Issue oncolytic virus systemic toxicity tumor microenvironment vaccinia virus Immunotherapy
Cytokines are promising for cancer treatment but face challenges like short half-lives, high-dose requirements, and systemic toxicity. Oncolytic viruses provide an ideal platform to overcome these limitations by delivering cytokines directly to tumor sites, enabling high local concentrations within the tumor microenvironment (TME). This study utilized an oncolytic vaccinia virus (oVV) to deliver interleukin-18 (IL-18) and its variants and assessed their antitumor effects across different tumor models. The non-secreted mature IL-18 mutein (nsmDR-18)-expressing oVV demonstrated potent antitumor efficacy with reduced systemic toxicity. It increased the expression of antitumor factors, including IL-2, interferon gamma (IFN-γ), granzyme B, and perforin, while expanding tumor-reactive CD39+CD103+CD8+ T cells and reducing severely exhausted PD-1+TIM-3+CD8+ T cells, thereby transforming immunologically “cold” tumors into “hot” tumors. However, nsmDR-18-expressing oVV treatment also elevated regulatory T cells (Tregs) and upregulated immune checkpoint molecules (PD-1, PD-L1, and CTLA-4). Combining nsmDR-18-expressing oVV with anti-CTLA-4 antibody significantly improved overall survival and induced systemic, tumor-specific antitumor immunity. These results highlight the potential of nsmDR-18-expressing oVV as a therapeutic strategy, supporting further exploration in clinical trials. [Display omitted] An oncolytic vaccinia virus delivering a non-secreted IL-18 mutein (nsmDR-18) enhances antitumor immunity by activating CD8+ T cells and reshaping the tumor microenvironment. Combination with anti-CTLA-4 further improves efficacy, offering a promising strategy to convert “cold” tumors into “hot” and induce durable, tumor-specific immune responses.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Medicine, Research & Experimental
Oncology
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