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Updated: May 25, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Development of attenuated Orf virus as a safe oncolytic viral vector for nasopharyngeal carcinoma treatment
Yumiko Yamada1, Yu-Chih Wang2, Hao-Ping Liu3
1Graduate Institute of Microbiology and Public Health, College of Veterinary Medicine, National Chung Hsing University, Taichung, Taiwan.
Background:
Orf virus (ORFV) is gaining attention as a promising viral vector for cancer therapy because of its unique properties. Recent studies have shown that ORFV could be effective against various cancers, particularly nasopharyngeal carcinoma. This research explores the ability of wild-type ORFV and recombinant ORFVs, which lack specific virulence factors, to kill NPC cells and modulate the immune response.
Methods:
Two NPC cell lines, HK1 (from Hong Kong) and TW02 (from Taiwan), were infected with wild-type ORFV and two recombinant ORFVs lacking either vascular endothelial growth factor (VEGF) or chemokine binding protein (CBP) virulence factors. The oncolytic effects were evaluated by assessing cell death pathways, particularly pyroptosis, which was monitored through the cleavage of gasdermin E (GSDME). The activation of survival pathways, such as focal adhesion kinase (FAK) and AKT, was also analyzed. In addition, the influence of ORFV infection on natural killer (NK) cell recruitment and cytotoxicity was investigated. In vivo experiments were conducted in a xenograft mouse model in which HK1 tumors were used to evaluate the antitumor activity of wild-type ORFV and two deletion-mutant ORFVs.
Results:
Wild-type ORFV effectively killed NPC cells, especially HK1 cells. The recombinant ORFVs, despite being attenuated by the loss of VEGF or CBP, retained the ability to infect and cause NPC cell death, with the CBP-deleted virus showing notable effectiveness in HK1 cells. Early ORFV infection led to pyroptosis via GSDME cleavage, causing cell detachment and a reduction in FAK and AKT activation. ORFV also enhanced NK cell recruitment and boosted NK cell-mediated cytotoxicity in infected NPC cells. In the HK1 xenograft model, CBP-deleted ORFV significantly inhibited tumor growth.
Conclusion:
ORFV, particularly the wild-type and CBP-deleted variants, has significant potential as an oncolytic viral vector for NPC therapy. It induces cell death via pyroptosis and enhances immune-mediated tumor cell destruction through NK cells. The attenuated CBP-deleted ORFV offers a safer and effective option for cancer treatment, making it a promising candidate for future therapeutic applications.
Insights
Orf virus (ORFV) shows promise for nasopharyngeal carcinoma (NPC) therapy, effectively killing cancer cells and enhancing immune responses. Attenuated ORFV variants, like the CBP-deleted one, offer a safer and potent oncolytic viral vector option.
Area of Science:
- Oncolytic virology
- Cancer immunotherapy
- Virology
Background:
- Orf virus (ORFV) is emerging as a potential viral vector for cancer therapy.
- ORFV demonstrates efficacy against various cancers, including nasopharyngeal carcinoma (NPC).
- This study investigates ORFV's oncolytic capabilities and immune-modulating effects in NPC.
Purpose of the Study:
- To evaluate the oncolytic potential of wild-type and engineered ORFVs against NPC cells.
- To assess the impact of ORFV infection on cancer cell death pathways, specifically pyroptosis.
- To determine ORFV's influence on natural killer (NK) cell activity and in vivo tumor suppression.
Main Methods:
- Infection of NPC cell lines (HK1, TW02) with wild-type and recombinant ORFVs (ΔVEGF, ΔCBP).
- Analysis of cell death (pyroptosis via GSDME cleavage) and survival pathways (FAK, AKT).
- Assessment of NK cell recruitment and cytotoxicity; in vivo xenograft mouse model studies.
Main Results:
- Wild-type ORFV effectively induced NPC cell death, particularly in HK1 cells.
- Recombinant ORFVs, including the CBP-deleted variant, retained oncolytic activity against NPC cells.
- ORFV triggered pyroptosis, reduced survival signaling, enhanced NK cell activity, and inhibited tumor growth in vivo.
Conclusions:
- ORFV, especially wild-type and CBP-deleted strains, holds significant potential as an oncolytic viral vector for NPC treatment.
- ORFV induces cancer cell death via pyroptosis and boosts anti-tumor immunity through NK cell activation.
- The attenuated CBP-deleted ORFV presents a safer and effective therapeutic candidate for nasopharyngeal carcinoma.
