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Intratumoral PD-1-directed IL-2 expression via oncolytic vaccinia virus elicits superior antitumor effects with enhanced safety
Journal article   Open access   Peer reviewed

Intratumoral PD-1-directed IL-2 expression via oncolytic vaccinia virus elicits superior antitumor effects with enhanced safety

Lingjuan Chen, Junjie Ye, Sefali Patel, Pingpo Ming, Chunyan Li, Julia Waltermire, Jinshun Zhao, Jinghua Ren, David L Bartlett and Zuqiang Liu
Journal for immunotherapy of cancer, v 14(3), e011340
18 Mar 2026
DOI: https://doi.org/10.1136/jitc-2024-011340
PMID: 41850740
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1136/jitc-2024-011340View
Published, Version of Record (VoR) Open CC BY-NC V4.0

Abstract

Cytokine Immune Checkpoint Inhibitor Oncolytic and local immunotherapy Oncolytic virus Tumor microenvironment - TME Gene Therapy
Background Cancer immunotherapy has revolutionized treatment, offering new hope for patients with previously hard-to-treat cancers. However, many solid tumors are classified as non-inflamed, meaning they are less responsive to immunotherapies. This underscores the need for novel strategies to transform these non-inflamed tumors into immune-inflamed ones. Oncolytic viruses, particularly when engineered, hold promise for stimulating immune responses and transforming these tumors. Cytokines, in particular, are promising for arming these viruses. Immune checkpoint inhibition, especially targeting the programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway, has been groundbreaking. In this study, we hypothesize that an oncolytic vaccinia virus (oVV) expressing a fusion protein of the PD-1 ectodomain and interleukin (IL)-2 (vvDD-PD-1ecto-R-IL-2) could mimic the combined effects of anti-PD-L1 antibodies and IL-2, transforming non-inflamed tumors and enhancing antitumor effects while minimizing the toxicity associated with systemic IL-2. Methods We generated the vvDD-PD-1ecto-R-IL-2 oncolytic virus and confirmed transgene expression through reverse transcription quantitative PCR (RT-qPCR), ELISA and flow cytometry. The antitumor efficacy and safety of vvDD-PD-1ecto-R-IL-2 were evaluated in murine tumor models. The underlying mechanisms of action were investigated using RT-qPCR, ELISA and flow cytometry. Results Our data demonstrate that the vvDD-PD-1ecto-R-IL-2 elicited significant antitumor effects, though the PD-1 ectodomain did not fully mimic the function of anti-PD-L1 antibodies, likely due to the elevated PD-L1 levels following oVV infection. However, PD-1 successfully directed IL-2 to associate with the cell membrane via PD-1ecto-R-IL-2/PD-L1 interaction, minimizing systemic toxicity. The accumulated IL-2 in the tumor microenvironment led to an increase in antitumor factors, including interferon (IFN)-γ, granzyme B, and perforin, while reducing protumor factors such as vascular endothelial growth factor and prostaglandin-endoperoxide synthase 2. Furthermore, treatment with the vvDD-PD-1ecto-R-IL-2 promoted the expansion of tumor-infiltrating stem-like CD8+ T cells (CD8+TCF-1+), as well as functional CD8+ T-cell subsets, including IFN-γ+CD8+, GzmB+CD8+, CD107a+CD8+, and perforin+CD8+, and reduced the presence of severely exhausted PD-1+TIM-3+CD8+ T cells, PD-1+LAG-3+CD8+ T cells and PD-1+TIGIT+CD8+ T cells, thereby transforming immunologically non-inflamed tumors into immune-inflamed tumors. Conclusions Our findings suggest that PD-1-directed IL-2 delivered via oVV is both safe and effective, making it a promising candidate for clinical translation.

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Collaboration types
Domestic collaboration
International collaboration
Web of Science research areas
Immunology
Oncology
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