A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer
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...
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Frontiers Media S.A.
2025-01-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1492464/full |
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| author | Lijuan Chen Lijuan Chen Pengju Wang Carmela Di Gioia Ming Yuan Zhe Zhang Jinxin Miao Wenli Yan Guanghao Zhao Yangyang Jia Na Wang Zhongxian Zhang Haoran Guo Giulia Marelli Louisa Chard Dunmall Nicholas R. Lemoine Nicholas R. Lemoine Yaohe Wang Yaohe Wang |
| author_facet | Lijuan Chen Lijuan Chen Pengju Wang Carmela Di Gioia Ming Yuan Zhe Zhang Jinxin Miao Wenli Yan Guanghao Zhao Yangyang Jia Na Wang Zhongxian Zhang Haoran Guo Giulia Marelli Louisa Chard Dunmall Nicholas R. Lemoine Nicholas R. Lemoine Yaohe Wang Yaohe Wang |
| author_sort | Lijuan Chen |
| collection | DOAJ |
| description | 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 treatment option for patients. |
| format | Article |
| id | doaj-art-b31165ccbde24f53b3adccbe08f25a7b |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-b31165ccbde24f53b3adccbe08f25a7b2025-01-07T06:51:14ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-01-011510.3389/fimmu.2024.14924641492464A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancerLijuan Chen0Lijuan Chen1Pengju Wang2Carmela Di Gioia3Ming Yuan4Zhe Zhang5Jinxin Miao6Wenli Yan7Guanghao Zhao8Yangyang Jia9Na Wang10Zhongxian Zhang11Haoran Guo12Giulia Marelli13Louisa Chard Dunmall14Nicholas R. Lemoine15Nicholas R. Lemoine16Yaohe Wang17Yaohe Wang18Department of Oncology, the Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, ChinaHenan International Joint Laboratory of Lung Cancer Biology and Therapeutics, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaCentre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomCentre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaCentre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomCentre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaCentre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, ChinaCentre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United KingdomOncolytic 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 treatment option for patients.https://www.frontiersin.org/articles/10.3389/fimmu.2024.1492464/fullVaccinia viruslung cancerinterleukin-12soluble PD-1immune checkpoint inhibitoroncolytic therapy |
| spellingShingle | Lijuan Chen Lijuan Chen Pengju Wang Carmela Di Gioia Ming Yuan Zhe Zhang Jinxin Miao Wenli Yan Guanghao Zhao Yangyang Jia Na Wang Zhongxian Zhang Haoran Guo Giulia Marelli Louisa Chard Dunmall Nicholas R. Lemoine Nicholas R. Lemoine Yaohe Wang Yaohe Wang A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer Frontiers in Immunology Vaccinia virus lung cancer interleukin-12 soluble PD-1 immune checkpoint inhibitor oncolytic therapy |
| title | A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer |
| title_full | A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer |
| title_fullStr | A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer |
| title_full_unstemmed | A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer |
| title_short | A novel oncolytic Vaccinia virus armed with IL-12 augments antitumor immune responses leading to durable regression in murine models of lung cancer |
| title_sort | novel oncolytic vaccinia virus armed with il 12 augments antitumor immune responses leading to durable regression in murine models of lung cancer |
| topic | Vaccinia virus lung cancer interleukin-12 soluble PD-1 immune checkpoint inhibitor oncolytic therapy |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2024.1492464/full |
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