Systemic cancer therapy with engineered adenovirus that evades innate immunity

Area of Science:

• Virology
• Immunology
• Oncology
• Biotechnology

Background:

• Oncolytic virus therapy offers promise for incurable cancers.
• Intravascular delivery faces challenges from blood factors causing inactivation and toxicity.
• Human adenovirus species C (HAdv-C5) is rapidly inactivated by IgM antibodies and Factor X upon intravenous administration, leading to liver toxicity.

Purpose of the Study:

• To engineer an oncolytic adenovirus resistant to blood inactivation and toxicity for improved intravenous delivery.
• To understand the interaction of HAdv-C5 with blood components, specifically IgM binding to the hexon protein's hypervariable region 1 (HVR1).

Main Methods:

• Compound targeted mutagenesis of the HAdv-C5 hexon protein's HVR1 and other functional sites.
• High-resolution cryo-electron microscopy to determine the structure of the engineered adenovirus vector (Ad5-3M).
• In vivo studies in mice with lung cancer to assess Ad5-3M's efficacy, biodistribution, and toxicity after intravenous delivery.

Main Results:

• Engineered Ad5-3M demonstrated resistance to inactivation by blood factors.
• Ad5-3M avoided sequestration in liver macrophages and did not trigger hepatotoxicity.
• Intravenous delivery of Ad5-3M resulted in viral replication in tumor cells, suppressed tumor growth, and prolonged survival in preclinical lung cancer models.

Conclusions:

• Targeted mutagenesis of capsid functional sites is a generalizable strategy to create "designer" oncolytic viruses with enhanced therapeutic properties.
• Ad5-3M represents a promising candidate for improved oncolytic virotherapy via systemic delivery.
• This approach allows tailoring virus interactions with the immune system to overcome delivery barriers.