Mediation of antitumor activity by AZD4820 oncolytic vaccinia virus encoding IL-12

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Cancer research

Background:

• Oncolytic viruses selectively target tumor cells, showing clinical promise.
• Interleukin-12 (IL-12) is a cytokine that activates immune cells and reprograms the tumor microenvironment.

Purpose of the Study:

• To engineer AZD4820, a vaccinia virus expressing IL-12, to enhance antitumor immunity.
• To evaluate the efficacy of AZD4820 in preclinical cancer models, particularly those resistant to immune checkpoint inhibition.

Main Methods:

• In vitro testing of AZD4820 on human tumor cell lines for oncolytic activity and IL-12 expression.
• In vivo studies using murine IL-12 surrogate virus in MC38 and CT26 tumor models.
• Assessment of interferon-gamma (IFN-γ) levels and complete response rates.
• Combination therapy with AZD4820 and anti-PD-L1 antibody.

Main Results:

• AZD4820 demonstrated broad in vitro oncolytic activity and IL-12 expression.
• The murine IL-12 surrogate virus showed significant antitumor activity in resistant tumor models.
• AZD4820 treatment upregulated IFN-γ compared to control vaccinia virus (VACV)-luciferase.
• Complete response was observed in 60% of mice treated with AZD4820 surrogate in the CT26 model, versus 0% in controls.
• Combination therapy enhanced tumor-specific T-cell immunity.

Conclusions:

• Vaccinia virus-delivered IL-12 (AZD4820) exhibits potent oncolytic activity and immune stimulation.
• AZD4820 demonstrates efficacy in preclinical models unresponsive to immune checkpoint blockade.
• Combination of AZD4820 with immune checkpoint inhibitors can elicit robust antitumor immunity.