Tailoring an intravenously injectable oncolytic virus for augmenting radiotherapy

Area of Science:

• Oncology
• Virology
• Immunology
• Materials Science

Background:

• Oncolytic viruses (OVs) combined with radiotherapy (RT) show therapeutic promise but face challenges in delivery and efficacy.
• Current limitations include poor intravenous delivery, rapid clearance, and insufficient tumor cell death induction by RT.
• Enhancing viral infectivity and RT-induced DNA damage is crucial for improved cancer treatment outcomes.

Purpose of the Study:

• To develop an oncolytic adenovirus (AD) formulation, RadioOnco (AD@PSSP), for enhanced intravenous delivery, infectivity, and synergistic efficacy with RT.
• To investigate the role of a multifunctional polyethylenimine (PEI)-selenium-polyethylene glycol (PEG) (PSSP) coating in improving viral delivery and RT response.
• To evaluate the potential of RadioOnco to overcome RT resistance, target distant metastases, and stimulate anti-tumor immune responses.

Main Methods:

• Development of an oncolytic adenovirus (AD) surface-modified with a multifunctional PEI-selenium-PEG (PSSP) coating, termed RadioOnco (AD@PSSP).
• Evaluation of AD@PSSP's intravenous delivery, tumor targeting, and viral shielding capabilities.
• Assessment of AD@PSSP's impact on RT-induced DNA damage by measuring DNA repair protein expression (CHEK1, CDK1).
• Analysis of immune responses, including antigen presentation and T-cell activation, in animal models.

Main Results:

• RadioOnco demonstrated enhanced intravenous delivery, tumor targeting, and protection from rapid clearance.
• The PSSP coating facilitated PEI exposure, increasing AD infectivity and enhancing RT-induced DNA damage by inhibiting DNA repair proteins.
• RadioOnco treatment led to robust anti-tumor immune responses by capturing and delivering RT-induced antigens.
• Animal models showed that RadioOnco overcame RT resistance, targeted distant metastases, and induced long-term immunity, addressing tumor recurrence.

Conclusions:

• RadioOnco, an intravenously injectable oncolytic adenovirus, significantly enhances RT synergy through surface modification with multifunctional PSSP materials.
• This formulation improves viral delivery, boosts RT-induced DNA damage, and activates potent anti-tumor immunity.
• RadioOnco offers a promising strategy for overcoming RT resistance and addressing metastatic disease, potentially leading to long-term disease control.