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

作者：Yujing Xuan, Wenyi Yan, Rui Wang, Xibin Wang, Yu Guo, Huilin Dun, Ziyan Huan, Lihua Xu, Ruxia Han, Xianlei Sun, Lingling Si, Nicholas R. Lemoine, Yaohe Wang, Pengju Wang · 发表于：Frontiers in Immunology · 年份：2025 · DOI：10.3389/fimmu.2024.1506632 · 被引用次数：17 · 研究领域：Virus-based gene therapy research、CAR-T cell therapy research、Cancer Research and Treatments

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 checkpoi...