Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer
<b>Objectives:</b> Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (...
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2025-04-01
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| author | Wenyi Yan Yujing Xuan Ruimin Wang Ziyan Huan Yu Guo Huilin Dun Lihua Xu Ruxia Han Xianlei Sun Lingling Si Nicholas Robert Lemoine Yaohe Wang Pengju Wang |
| author_facet | Wenyi Yan Yujing Xuan Ruimin Wang Ziyan Huan Yu Guo Huilin Dun Lihua Xu Ruxia Han Xianlei Sun Lingling Si Nicholas Robert Lemoine Yaohe Wang Pengju Wang |
| author_sort | Wenyi Yan |
| collection | DOAJ |
| description | <b>Objectives:</b> Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-7 (IL-7), designed to enhance anti-tumor immunity and synergize with immune checkpoint inhibitors. <b>Methods:</b> VVL-GL7 was constructed through CRISPR/Cas9-mediated knockout of TK and A49 genes, combined with the simultaneous insertion of dual cytokine-encoding cassettes. Anti-tumor efficacy was evaluated in vitro and in vivo using C57BL/6 mouse and Syrian hamster pancreatic cancer models. Comprehensive immune profiling evaluated CD8<sup>+</sup> T-cell and macrophage infiltration dynamics while simultaneously assessing memory T-cell differentiation patterns using flow cytometry. Preclinical combination studies of VVL-GL7 and the PD-1 immune checkpoint inhibitor were systematically evaluated in a syngeneic pancreatic cancer model. <b>Results:</b> VVL-GL7 exhibited potent oncolytic activity, inducing significant tumor regression in both preclinical models. VVL-GL7 therapy significantly augmented CD8<sup>+</sup> T-cell and macrophage infiltration within the tumor microenvironment, while concomitantly driving memory T-cell differentiation. The synergistic effects of VVL-GL7 and the PD-1 blockade further improved therapeutic outcomes, resulting in significantly higher tumor remission rates compared to monotherapy and achieving complete tumor regression in pancreatic cancer models. <b>Conclusions:</b> VVL-GL7 reprograms the immunosuppressive tumor microenvironment and synergizes with anti-PD-1 antibodies to overcome resistance in pancreatic cancer. |
| format | Article |
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| institution | DOAJ |
| issn | 2227-9059 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Biomedicines |
| spelling | doaj-art-e42abfffbe3b4c92ae91eeeffd9375f72025-08-20T03:14:27ZengMDPI AGBiomedicines2227-90592025-04-0113488210.3390/biomedicines13040882Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic CancerWenyi Yan0Yujing Xuan1Ruimin Wang2Ziyan Huan3Yu Guo4Huilin Dun5Lihua Xu6Ruxia Han7Xianlei Sun8Lingling Si9Nicholas Robert Lemoine10Yaohe Wang11Pengju Wang12Sino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaDepartment of Pathology, Zhengzhou People’s Hospital, Fifth Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450003, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, ChinaSino-British Research Centre for Molecular Oncology, National Centre for International Research in Cell and Gene Therapy, State Key Laboratory of Esophageal Cancer Prevention & Treatment, School of Basic Medical Sciences, Academy of Medical Sciences, Zhengzhou University, Zhengzhou 450001, China<b>Objectives:</b> Pancreatic cancer remains a therapeutic challenge due to its immunosuppressive microenvironment and treatment resistance. This study aimed to develop a novel recombinant oncolytic vaccinia virus (VVL-GL7) co-expressing granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-7 (IL-7), designed to enhance anti-tumor immunity and synergize with immune checkpoint inhibitors. <b>Methods:</b> VVL-GL7 was constructed through CRISPR/Cas9-mediated knockout of TK and A49 genes, combined with the simultaneous insertion of dual cytokine-encoding cassettes. Anti-tumor efficacy was evaluated in vitro and in vivo using C57BL/6 mouse and Syrian hamster pancreatic cancer models. Comprehensive immune profiling evaluated CD8<sup>+</sup> T-cell and macrophage infiltration dynamics while simultaneously assessing memory T-cell differentiation patterns using flow cytometry. Preclinical combination studies of VVL-GL7 and the PD-1 immune checkpoint inhibitor were systematically evaluated in a syngeneic pancreatic cancer model. <b>Results:</b> VVL-GL7 exhibited potent oncolytic activity, inducing significant tumor regression in both preclinical models. VVL-GL7 therapy significantly augmented CD8<sup>+</sup> T-cell and macrophage infiltration within the tumor microenvironment, while concomitantly driving memory T-cell differentiation. The synergistic effects of VVL-GL7 and the PD-1 blockade further improved therapeutic outcomes, resulting in significantly higher tumor remission rates compared to monotherapy and achieving complete tumor regression in pancreatic cancer models. <b>Conclusions:</b> VVL-GL7 reprograms the immunosuppressive tumor microenvironment and synergizes with anti-PD-1 antibodies to overcome resistance in pancreatic cancer.https://www.mdpi.com/2227-9059/13/4/882oncolytic virusvaccinia virusGM-CSFIL-7pancreatic cancer |
| spellingShingle | Wenyi Yan Yujing Xuan Ruimin Wang Ziyan Huan Yu Guo Huilin Dun Lihua Xu Ruxia Han Xianlei Sun Lingling Si Nicholas Robert Lemoine Yaohe Wang Pengju Wang Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer Biomedicines oncolytic virus vaccinia virus GM-CSF IL-7 pancreatic cancer |
| title | Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer |
| title_full | Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer |
| title_fullStr | Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer |
| title_full_unstemmed | Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer |
| title_short | Oncolytic Vaccinia Virus Armed with GM-CSF and IL-7 Enhances Antitumor Immunity in Pancreatic Cancer |
| title_sort | oncolytic vaccinia virus armed with gm csf and il 7 enhances antitumor immunity in pancreatic cancer |
| topic | oncolytic virus vaccinia virus GM-CSF IL-7 pancreatic cancer |
| url | https://www.mdpi.com/2227-9059/13/4/882 |
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