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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Directed natural evolution generates a next-generation oncolytic virus with a high potency and safety profile
1Department of Pharmacology, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
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.
Insights
Directed natural evolution created a next-generation oncolytic virus (NGOVM) that significantly enhances cancer cell killing. This engineered virus shows a broad antitumor spectrum and is well-tolerated, offering a promising new cancer therapy.
Area of Science:
- Virology
- Oncology
- Molecular Biology
Background:
- Oncolytic viruses (OVs) are promising multi-mechanistic cancer therapeutics.
- Attenuating virulence for OV development often reduces tumor cell killing efficacy.
Purpose of the Study:
- To develop a next-generation oncolytic virus (NGOVM) with enhanced tumor-killing capabilities.
- To investigate the mechanisms underlying the improved oncolytic effect and safety profile.
Main Methods:
- Directed natural evolution of an oncolytic virus (M1) in refractory colorectal cancer cells (HCT-116).
- Identification of critical mutations in E2 and nsP3 genes.
- Assessment of viral entry, antiviral response antagonism, and in vivo safety in rodents and nonhuman primates.
Main Results:
- Generated NGOVM with up to a 9690-fold increase in oncolytic effect.
- NGOVM demonstrated a broader antitumor spectrum across various solid tumors.
- Identified mutations enhance viral entry via Mxra8 binding and inhibit PKR/STAT1 antiviral pathways.
- NGOVM exhibited good tolerability in preclinical safety studies.
Conclusions:
- Directed natural evolution is an effective strategy for developing next-generation OVs.
- NGOVM possesses enhanced efficacy, a broad spectrum, and favorable safety for cancer therapy.
- This approach offers a generalizable method for creating improved oncolytic viruses.
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