A PD-L1 tropism-expanded oncolytic adenovirus enhanced gene delivery efficiency and anti-tumor effects

Area of Science:

• Oncolytic virotherapy
• Molecular engineering
• Cancer research

Background:

• Adenovirus serotype 5 (Ad5)-mediated virotherapy is a promising cancer treatment.
• Limited coxsackievirus and adenovirus receptor (CAR) expression on cancer cells restricts Ad infectivity.
• Novel strategies are needed to enhance oncolytic adenovirus (Ad) efficacy.

Purpose of the Study:

• To develop a novel tropism-modified oncolytic adenovirus, ZD55-F-HI-sPD-1-EGFP, for improved cancer cell targeting.
• To enhance Ad infectivity in cancer cells with low CAR expression by incorporating a PD-1 epitope.
• To evaluate the efficacy of this modified Ad in vitro and in vivo.

Main Methods:

• Engineered an oncolytic Ad (ZD55-F-HI-sPD-1-EGFP) with a PD-1 epitope in the fiber HI-loop.
• Confirmed Fiber-sPD-1 trimerization via immunoblot analysis.
• Assessed viral infection, gene transduction, and progeny virus production in PD-L1-positive cancer cells.
• Evaluated anti-tumor effects in vivo.

Main Results:

• ZD55-F-HI-sPD-1-EGFP demonstrated significantly improved viral infection and gene transduction in PD-L1-positive cancer cells.
• Cellular uptake was mediated by both CAR and PD-L1 at high viral doses.
• Incorporation of sPD-1 did not affect oncolytic Ad replication capacity.
• In vivo studies showed enhanced viral infection and significant anti-tumor efficacy.

Conclusions:

• Tropism modification of oncolytic Ad by incorporating PD-1 epitopes can overcome CAR-dependent entry limitations.
• This strategy broadens the tropism of oncolytic Ads, enhancing their therapeutic potential against PD-L1-expressing cancers.
• Engineered oncolytic Ads offer a promising approach to improve cancer virotherapy outcomes.