Directed natural evolution generates a next-generation oncolytic virus with a high potency and safety profile

Li Guo, Cheng Hu, Yang Liu, Xiaoyu Chen, Deli Song, Runling Shen, Zhanzhen Liu, Xudong Jia, Qinfen Zhang, Yuanzhu Gao, Zhezhi Deng, Tao Zuo, Jun Hu, Wenbo Zhu, Jing Cai, Guangmei Yan, Jiankai Liang () and Yuan Lin ()
Additional contact information
Li Guo: Sun Yat-sen University
Cheng Hu: The Third Affiliated Hospital of Sun Yat-sen University
Yang Liu: Sun Yat-sen University
Xiaoyu Chen: Sun Yat-sen University
Deli Song: Sun Yat-sen University
Runling Shen: Sun Yat-sen University
Zhanzhen Liu: Sun Yat-sen University
Xudong Jia: Sun Yat-sen University
Qinfen Zhang: Sun Yat-sen University
Yuanzhu Gao: Sun Yat-sen University
Zhezhi Deng: National Key Clinical Department and Key Discipline of Neurology
Tao Zuo: Sun Yat-sen University
Jun Hu: Sun Yat-sen University
Wenbo Zhu: Sun Yat-sen University
Jing Cai: Sun Yat-sen University
Guangmei Yan: Sun Yat-sen University
Jiankai Liang: Sun Yat-sen University
Yuan Lin: Sun Yat-sen University

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Oncolytic viruses (OVs) represent a type of encouraging multi-mechanistic drug for the treatment of cancer. However, attenuation of virulence, which is generally required for the development of OVs based on pathogenic viral backbones, is frequently accompanied by a compromised killing effect on tumor cells. By exploiting the property of viruses to evolve and adapt in cancer cells, we perform directed natural evolution on refractory colorectal cancer cell HCT-116 and generate a next-generation oncolytic virus M1 (NGOVM) with an increase in the oncolytic effect of up to 9690-fold. The NGOVM has a broader antitumor spectrum and a more robust oncolytic effect in a range of solid tumors. Mechanistically, two critical mutations are identified in the E2 and nsP3 genes, which accelerate the entry of M1 virus by increasing its binding to the Mxra8 receptor and antagonize antiviral responses by inhibiting the activation of PKR and STAT1 in tumor cells, respectively. Importantly, the NGOVM is well tolerated in both rodents and nonhuman primates. This study implies that directed natural evolution is a generalizable approach for developing next-generation OVs with an expanded scope of application and high safety.

Date: 2023
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DOI: 10.1038/s41467-023-39156-3

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