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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1492464

A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer

Provisionally accepted
Lijuan Chen Lijuan Chen 1,2Pengju Wang Pengju Wang 3Carmela Di Gioia Carmela Di Gioia 4Ming Yuan Ming Yuan 4Zhe Zhang Zhe Zhang 3Jinxin Miao Jinxin Miao 3Wenli Yan Wenli Yan 3Guanghao Zhao Guanghao Zhao 3Yangyang Jia Yangyang Jia 3Wang Na Wang Na 3Zhongxian Zhang Zhongxian Zhang 3Haoran Guo Haoran Guo 3Giulia Marelli Giulia Marelli 4Louisa Chard Dunmall Louisa Chard Dunmall 4Nicholas R Lemoine Nicholas R Lemoine 4yaohe Wang yaohe Wang 3,4*
  • 1 ＆Henan Cancer Hospital, Zhengzhou, 450008, China., Department of Medical Oncology, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
  • 2 Henan International Joint Laboratory of Lung Cancer Biology and Therapeutics, Zhengzhou, 450008, China., Zhengzhou, China
  • 3 Center for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan Province, China
  • 4 Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, England, United Kingdom

The final, formatted version of the article will be published soon.

    Oncolytic vaccinia viruses (VVs) are potent stimulators of the immune system and induce immune-mediated tumor clearance and long-term surveillance against tumor recurrence. As such they are ideal treatment modalities for solid tumors including lung cancer. Here, we investigated the use of VVL-m12, a next-generation, genetically modified, interleukin-12 (IL-12)-armed VV, as a new therapeutic strategy to treat murine models of lung cancer and as a mechanism of increasing lung cancer sensitivity to antibody against programmed cell death protein 1 (α-PD1) therapy. The cytotoxicity and replication of VVL-m12, VVL-h12 and control VVs were assessed in lung cancer cell lines. Subcutaneous lung cancer mouse models were established to investigate the anti-tumor activity of the viruses after intratumoral delivery in an immunocompetent disease model. Synergy with α-PD1 or a VV armed with soluble PD-1 (VV-sPD1) was investigated and functional mechanisms behind efficacy probed. Tumor-targeted VVL-m12 replicated to high levels, was cytotoxic in lung cancer cell lines. VVL-m12 demonstrated superior antitumor efficacy in subcutaneous lung cancer models compared with other VVs examined. Importantly, rational combination of VVL-m12 and PD-1 blockade worked synergistically to significantly enhance survival of animals and safely cured lung cancer with no evidence of recurrence. VVL-m12 therapy induced increased intratumoral infiltration of CD4+ and CD8+ T cells and was able to clear tumor at early time points via increased induction and infiltration of effector T cells and central memory T cells (TCM). In addition, VVL-m12 increased dendritic cell activation, induced polarization of M2 macrophages towards an M1 phenotype, and inhibited tumor angiogenesis in vivo.These results demonstrate that VVL-12 has strong potential as a safe and effective antitumor therapeutic for lung cancer. Importantly, VVL-12 can sensitize lung cancers to α-PD1 antibody therapy, and the combined regime creates a highly effective

    Keywords: Intratumoral, I.P: intraperitoneal, VVL-m12: VVLΔTK-STCΔN1L-murineIL12, VVL-h12: VVLΔTK-STCΔN1L-humanIL12, VVL-m21: VVLΔTK-STCΔN1L-murineIL21, VV CTRL: VVLΔTK-STCΔN1L, VV-sPD1: VVΔTK-ΔN1L-mouse soluble PD-1, TME: tumor microenvironment

    Received: 07 Sep 2024; Accepted: 10 Dec 2024.

    Copyright: © 2024 Chen, Wang, Gioia, Yuan, Zhang, Miao, Yan, Zhao, Jia, Na, Zhang, Guo, Marelli, Chard Dunmall, Lemoine and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: yaohe Wang, Center for Cell and Gene Therapy, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052, Henan Province, China

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