Oncolytic herpes simplex viruses designed for targeted treatment of EGFR-bearing tumors

Area of Science:

• Oncolytic virotherapy
• Molecular engineering
• Cancer therapeutics

Background:

• Oncolytic herpes simplex viruses (oHSVs) are promising cancer agents.
• Targeting primary tumors and metastases requires both intratumoral and systemic delivery.
• Engineering viral glycoproteins enhances tumor specificity via tumor-specific cell surface proteins.

Purpose of the Study:

• To compare engineered oHSVs with different ligands (scFv, affibody, VHH) at various positions on glycoprotein D (gD).
• To evaluate the efficacy of these retargeted oHSVs for EGFR-expressing tumors.
• To assess the potential for systemic delivery of targeted oHSVs for metastatic disease.

Main Methods:

• Engineering oHSVs by incorporating single-chain antibody (scFv), affibody, or VHH antibody ligands into glycoprotein D (gD).
• Comparing the performance of scFv-, affibody-, and VHH-retargeted oHSVs.
• Evaluating EGFR-specific tumor cell entry, spread, and killing in vitro.
• Assessing long-term tumor-specific virus replication and tumor growth reduction in vivo after intravenous and intratumoral delivery.

Main Results:

• VHH and affibody ligands mediated enhanced EGFR-specific tumor cell entry, spread, and killing compared to scFv.
• Engineered oHSVs enabled long-term tumor-specific virus replication following intravenous delivery in vivo.
• VHH-retargeted oHSVs reduced tumor growth upon intravenous injection and achieved complete tumor destruction after intratumoral injection.

Conclusions:

• VHH and affibody ligands represent an improvement over scFv for retargeting oHSVs to EGFR-expressing cells.
• Enhanced targeted oHSV design is crucial for effective and safe systemic administration via bloodstream.
• These findings advance the development of tumor-specific oHSVs for treating metastatic cancer.