An oncolytic HAdV-5 with reduced surface charge combines diminished toxicity and improved tumor targeting

Area of Science:

• Oncolytic virotherapy
• Gene therapy vectors
• Cancer research

Background:

• Human adenovirus type 5 (HAdV-5)-based oncolytic viruses are promising cancer therapeutics.
• Systemic administration faces challenges including poor tumor targeting, off-target organ transduction, and significant liver toxicity due to HAdV-5 tropism.

Purpose of the Study:

• To engineer a novel HAdV-5-based oncolytic vector with enhanced tumor-targeting and reduced systemic toxicity.
• To evaluate the *in vitro* and *in vivo* performance of the modified vector, focusing on tropism, tumor-to-liver ratio, and safety.

Main Methods:

• Genetic modification of the HAdV-5 hexon protein to reduce negative surface charge, creating HAdV-5-HexPos3.
• Ablation of Coxsackie and adenovirus receptor (CAR) binding in the modified vector (HAdV-5-HexPos3_ΔCAR).
• In vitro transduction assays in cancer cell lines and in vivo studies in tumor-bearing NSG mice using intravenous administration.

Main Results:

• HAdV-5-HexPos3_ΔCAR demonstrated CAR-independent, enhanced cancer cell transduction *in vitro*.
• Intravenous administration in mice showed significantly reduced off-target organ tropism and a 29-fold higher tumor-to-liver vector load ratio compared to control.
• A conditionally replicating HAdV-5-HexPos3_ΔCAR vector was well-tolerated, unlike the control vector which induced severe hepatotoxicity.

Conclusions:

• The HAdV-5-HexPos3_ΔCAR vector platform offers a promising strategy for developing safer and more effective HAdV-5-based oncolytic viruses.
• Reduced systemic toxicity and improved intratumoral vector accumulation are key advantages for enhanced anti-cancer therapy.