Complementary dual-virus strategy drives synthetic target and cognate T-cell engager expression for...

Area of Science:

• Oncolytic virology
• Cancer immunotherapy
• Molecular engineering

Background:

• Targeted antineoplastic immunotherapies show promise but face resistance due to target absence or shedding.
• This limits treatment efficacy and excludes certain tumors from candidacy.
• Developing strategies to overcome resistance is crucial for expanding immunotherapy applications.

Purpose of the Study:

• To engineer an oncolytic virus to express a truncated HER2 antigen (HER2T) for targeted therapy.
• To evaluate the efficacy of HER2T-expressing vesicular stomatitis virus (VSVΔ51) in combination with trastuzumab-based therapies.
• To assess a dual-virus strategy combining VSVΔ51-HER2T with a HER2-targeted T-cell engager for enhanced anti-tumor immunity.

Main Methods:

• Engineering VSVΔ51 to express a truncated HER2 (HER2T) lacking signaling capabilities.
• Assessing HER2T surface expression on infected cells.
• Evaluating treatment efficacy with trastuzumab emtansine in vitro, ex vivo, and in vivo models.
• Combining VSVΔ51-HER2T with an oncolytic vaccinia virus expressing a HER2-targeted T-cell engager for in vivo studies.

Main Results:

• VSVΔ51 efficiently expressed HER2T on infected cell surfaces, simulating HER2-positive status.
• HER2T expression enabled effective treatment with trastuzumab emtansine.
• The dual-virus strategy demonstrated potent curative efficacy in vivo in mice.
• The combination leveraged CD3+ T-cell infiltrate for enhanced anti-tumor immunity.

Conclusions:

• Oncolytic viruses can be engineered to express tumor antigens, overcoming resistance to targeted therapies.
• This approach enhances compatibility with existing antibody-drug conjugates and T-cell engagers.
• Tailoring the tumor microenvironment with oncolytic viruses offers a promising strategy for improving cancer treatment outcomes.