Enhanced Anti-Tumor Response Elicited by a Novel Oncolytic Pseudorabies Virus Engineered with a PD-L1 Inhibitor
Guangtao Xiang1, Mengdong Wang1, Pu Wang2
1College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Abstract:
Oncolytic viruses combined with immunotherapy offer significant potential in tumor therapy. In this study, we engineered a further attenuated pseudorabies virus (PRV) vaccine strain that incorporates a PD-L1 inhibitor and demonstrated its promise as an oncolytic virus in tumor therapy. We first showed that the naturally attenuated PRV vaccine strain Bartha can efficiently infect tumor cells from multiple species, including humans, mice, and dogs in vitro. We then evaluated the safety and anti-tumor efficacy of this vaccine strain and its different single-gene deletion mutants using the B16-F10 melanoma mouse model. The TK deletion strain emerged as the optimal vector, and we inserted a PD-L1 inhibitor (iPD-L1) into it using CRISPR/Cas9 technology. Compared with the control, the recombinant PRV (rPRV-iPD-L1) exhibited more dramatic anti-tumor effects in the B16-F10 melanoma mouse model. Our study suggests that PRV can be developed not only as an oncolytic virus but also a powerful vector for expressing foreign genes to modulate the tumor microenvironment.
Insights
Engineered pseudorabies virus (PRV) effectively targets tumors. This modified virus, incorporating a PD-L1 inhibitor, shows significant anti-tumor effects, offering a promising new approach for cancer therapy.
Area of Science:
- Virology
- Immunology
- Oncology
Background:
- Oncolytic viruses and immunotherapy show promise in cancer treatment.
- Pseudorabies virus (PRV) vaccine strain Bartha can infect various tumor cells.
- Further attenuation and genetic modification of PRV are explored for enhanced therapeutic potential.
Purpose of the Study:
- To engineer an attenuated PRV strain as an oncolytic virus.
- To incorporate a PD-L1 inhibitor into the PRV vector for enhanced anti-tumor activity.
- To evaluate the safety and efficacy of the engineered oncolytic virus.
Main Methods:
- In vitro infection assays of PRV Bartha strain on tumor cells.
- In vivo evaluation of PRV safety and anti-tumor efficacy in a B16-F10 melanoma mouse model.
- CRISPR/Cas9 technology used to insert a PD-L1 inhibitor (iPD-L1) into the optimal PRV TK deletion mutant.
Main Results:
- PRV Bartha efficiently infected human, mouse, and dog tumor cells in vitro.
- The PRV TK deletion strain was identified as the optimal vector.
- The recombinant PRV expressing iPD-L1 (rPRV-iPD-L1) demonstrated significantly enhanced anti-tumor effects compared to controls in the B16-F10 model.
Conclusions:
- Attenuated PRV is a viable oncolytic virus candidate for cancer therapy.
- Engineered PRV can serve as a vector for expressing therapeutic genes, such as PD-L1 inhibitors.
- This approach holds potential for modulating the tumor microenvironment and improving cancer treatment outcomes.
