VAX014 Activates Tumor-Intrinsic STING and RIG-I to Promote the Development of Antitumor Immunity

Area of Science:

• Immunology
• Oncology
• Virology

Background:

• In situ immunization (ISI) enhances cancer immunity, but oncolytic viruses (OV) face limitations in STING/RIG-I-positive solid tumors due to type I IFN sensitivity.
• Stimulator of interferon genes (STING) and retinoic acid-inducible gene I (RIG-I) pathways are crucial in antiviral responses and tumor immunity.

Purpose of the Study:

• To investigate VAX014, a bacterial minicell-based ISI agent, for its efficacy in solid tumors, particularly those expressing STING and/or RIG-I.
• To elucidate the mechanism of action of VAX014 and its dependence on STING and RIG-I pathways.

Main Methods:

• Utilized pharmacologic, genetic, and in vivo approaches in mouse models with established syngeneic tumors.
• Analyzed human solid tumor datasets to assess STING and RIG-I co-expression prevalence and clinical relevance.

Main Results:

• Intratumoral VAX014 treatment achieved 100% tumor clearance in STING- and RIG-I-positive mouse models.
• VAX014's antitumor activity was dependent on both tumor-intrinsic STING/RIG-I and host-intrinsic STING.
• STING and RIG-I co-expression is common in human solid tumors and linked to clinical benefit.

Conclusions:

• VAX014 activates STING and RIG-I, differentiating it from OVs and enabling efficacy in STING/RIG-I-positive solid tumors.
• STING/RIG-I agonism is a key component of VAX014's mechanism of action.
• VAX014 represents a viable alternative to OV therapy for solid tumors, warranting further clinical investigation.