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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Vaccines and Molecular Therapeutics
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1506632

GM-CSF and IL-21-armed oncolytic vaccinia virus significantly enhances anti-tumor activity and synergizes with anti-PD1 immunotherapy in pancreatic cancer

Provisionally accepted
Pengju Wang Pengju Wang 1*Yujing Xuan Yujing Xuan 1Wenyi Yan Wenyi Yan 1Ruimin Wang Ruimin Wang 2Xibin Wang Xibin Wang 1Yu Guo Yu Guo 1Huilin Dun Huilin Dun 1Ziyan Huan Ziyan Huan 1Lihua Xu Lihua Xu 1Ruxia Han Ruxia Han 1Xianlei Sun Xianlei Sun 1Lingling Si Lingling Si 1Nicholas R Lemoine Nicholas R Lemoine 1Yaohe Wang Yaohe Wang 3
  • 1 Zhengzhou University, Zhengzhou, China
  • 2 Henan University of Chinese Medicine, Zhengzhou, Henan Province, China
  • 3 Queen Mary University of London, London, United Kingdom

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

    Pancreatic cancer is one of the most aggressive cancers and poses significant challenges to current therapies because of its complex immunosuppressive tumor microenvironment (TME). Oncolytic viruses armed with immunoregulatory molecules are promising strategies to overcome limited efficacy and target inaccessible and metastatic tumors. In this study, we constructed a tumor-selective vaccinia virus (VV) with deletions of the TK and A49 genes (VVLΔTKΔA49, VVL-DD) using CRISPR-Cas9-based homologous recombination. VVL-DD exhibited significant tumor selectivity in vitro and anti-tumor potency in vivo in a murine pancreatic cancer model.Then, VVL-DD was armed with an optimal combination of immunomodulatory molecules, granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-21 (IL-21), to produce VVL-GL21. VVL-GL21 induced significant tumor regression after intratumoral and systemic administration. Moreover, VVL-GL21 increased the infiltration of dendritic cells (DCs), macrophages, and T cells; induced DC maturation; increased the transition from M2 to M1 macrophages; improved the formation of immune memory; prevented tumor recurrence; and effectively bolstered the immune response against tumors in multiple key immune compartments.Interestingly, mice bearing-pancreatic cancer tumors treated with VVL-GL21 showed anti-tumor immunity against lung and colon cancer tumors. Importantly, treatment with VVL-GL21 enhanced the responsiveness of tumors to the immune checkpoint inhibitor anti-PD1. Taken together, VVL-GL21 remodels the suppressive TME and has powerful anti-tumor activities as monotherapy or in combination with anti-PD1 by intratumoral or systemic delivery for the treatment of pancreatic cancer. VVL-GL21 could be used as a therapeutic cancer vaccine.

    Keywords: oncolytic vaccinia virus, GM-CSF, IL-21, Pancreatic Cancer, Anti-PD1

    Received: 05 Oct 2024; Accepted: 10 Dec 2024.

    Copyright: © 2024 Wang, Xuan, Yan, Wang, Wang, Guo, Dun, Huan, Xu, Han, Sun, Si, 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: Pengju Wang, Zhengzhou University, Zhengzhou, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.