Enhanced antitumor efficacy of a novel oncolytic vaccinia virus encoding a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT)
Shuguang Zuo,
Min Wei,
Bohao He,
Anxian Chen,
Shiqun Wang,
Lingkai Kong,
Yenan Zhang,
Gang Meng,
Tiancheng Xu,
Jingyi Wu,
Fuming Yang,
Hailin Zhang,
Shibing Wang,
Ciliang Guo,
Junhua Wu,
Jie Dong,
Jiwu Wei
Affiliations
Shuguang Zuo
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Min Wei
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Bohao He
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Anxian Chen
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Shiqun Wang
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Lingkai Kong
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Yenan Zhang
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Gang Meng
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Tiancheng Xu
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Jingyi Wu
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Fuming Yang
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Hailin Zhang
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Shibing Wang
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Ciliang Guo
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Junhua Wu
Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Jie Dong
Corresponding authors.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Jiwu Wei
Corresponding authors.; Jiangsu Key Laboratory of Molecular Medicine, Medical School of Nanjing University, No. 22, Hankou Road, Nanjing 210093, China
Background: Oncolytic virotherapy with vaccinia virus (VV) can lead to effective anti-tumor immunity by turning “cold” tumors into “hot” tumors. However, its therapeutic potential is affected by the tumor's local immunosuppressive tumor microenvironment (TME). Therefore, it is necessary to explore the use of immune checkpoint inhibitors to arm oncolytic VVs to enhance their anti-tumor efficacy. Methods: A novel recombinant oncolytic VV, VV-α-TIGIT, which encoded a fully monoclonal antibody against T-cell immunoglobulin and ITIM domain (TIGIT) was generated by homologous recombination with a shuttle plasmid. The anti-tumor efficacy of the VV-α-TIGIT was investigated in several subcutaneous and ascites tumor models. Findings: The functional α-TIGIT was sufficiently produced and secreted by tumor cells infected with VV-α-TIGIT, which effectively replicated in tumor cells leading to significant oncolysis. Intratumoral injection of VV-α-TIGIT improved anti-tumor efficacy in several murine subcutaneous tumor models compared to VV-Control (without α-TIGIT insertion). Intraperitoneal injection of VV-α-TIGIT achieved approximately 70% of complete tumor regression in an ascites tumor model. At the same time, treatment with VV-α-TIGIT significantly increased the recruitment and activation of T cells in TME. Moreover, the in vivo anti-tumor activity of VV-α-TIGIT was largely dependent on CD8+ T cell-mediated immunity. Finally, the tumor-bearing mice cured of VV-α-TIGIT treatment resisted rechallenge with the same tumor cells, suggesting a long-term persistence of tumor-specific immunological memory. Interpretation: The recombinant oncolytic virus VV-α-TIGIT successfully combines the advantages of oncolytic virotherapy and intratumorally expression of immune checkpoint inhibitor against TIGIT. This novel strategy can provide information on the optimal design of novel antibody-armed oncolytic viruses for cancer immunotherapy. Funding: This work was supported by the National Natural Science Foundation of China (81773255, 81472820, and 81700037), the Science and Technology Innovation Foundation of Nanjing University (14913414), and the Natural Science Foundation of Jiangsu Province of China (BK20171098).
