Development of a versatile oncolytic virus platform for local intra-tumoural expression of therapeutic transgenes

Area of Science:

• Oncolytic virotherapy
• Gene therapy
• Adenovirus engineering

Background:

• Oncolytic viruses can be genetically modified to express therapeutic genes for enhanced anti-cancer activity.
• Modifying these viruses is challenging due to potential attenuation of viral activity or off-target transgene expression.
• Enadenotucirev is an oncolytic adenovirus that selectively replicates in tumor cells and is stable for intravenous delivery.

Purpose of the Study:

• To develop a readily modifiable virus platform based on enadenotucirev for cancer gene therapy.
• To create a system for efficient cloning and expression of transgenes within the enadenotucirev genome.
• To demonstrate the potential of this platform for delivering complex therapeutics, such as antibodies, to tumors.

Main Methods:

• Generated plasmids from the enadenotucirev genome for single-step cloning of transgene cassettes.
• Created reporter viruses to identify optimal cloning sites and transgene cassette designs.
• Inserted multiple genes into the enadenotucirev genome to encode full-length anti-VEGF antibodies.

Main Results:

• The platform enabled successful generation of reporter viruses and identification of effective transgene expression strategies.
• Transgene expression in tumor cells in vitro and in vivo did not affect the virus's oncolytic activity or tumor selectivity.
• Functional anti-VEGF antibodies were synthesized and secreted by infected tumor cells, demonstrating the platform's therapeutic potential.
• Viral particles were effectively delivered intravenously to disseminated orthotopic tumors.

Conclusions:

• The enadenotucirev platform provides a versatile and efficient system for engineering oncolytic viruses for cancer gene therapy.
• This approach overcomes challenges associated with transgene expression and delivery, enabling the development of complex therapeutic agents.
• The engineered viruses maintain oncolytic potency and tumor selectivity while delivering therapeutic payloads, offering a promising strategy for cancer treatment.