Enhanced Therapeutic Efficacy of a Novel Oncolytic Herpes Simplex Virus Type 2 Encoding an Antibody Against...

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Cancer research

Background:

• Immune checkpoint blockade (ICB) therapy shows limited efficacy in "cold" tumors.
• Combining ICB with oncolytic viruses or engineering viruses to express therapeutic factors can enhance efficacy.
• Programmed cell death 1 (PD-1) is a key immune checkpoint target.

Purpose of the Study:

• To engineer a novel oncolytic herpes simplex virus 2 (HSV2) encoding an anti-human PD-1 monoclonal antibody (oHSV2-aPD1).
• To evaluate the therapeutic efficacy of oHSV2-aPD1 in poorly immunogenic melanoma models.
• To assess the impact of oHSV2-aPD1 on the tumor microenvironment and systemic immunity.

Main Methods:

• Engineering of oHSV2-aPD1, an oncolytic HSV2 construct expressing an anti-PD-1 antibody.
• In vitro assessment of antibody expression in infected eukaryotic cells.
• In vivo therapeutic efficacy studies in poorly immunogenic melanoma mouse models.
• Analysis of immune cell activation and molecular changes in the tumor microenvironment and systemic circulation.

Main Results:

• oHSV2-aPD1 demonstrated detectable expression of a functional anti-PD-1 antibody.
• Therapeutic efficacy of oHSV2-aPD1 was superior to unmodified HSV2 or PD-1 blockade alone.
• oHSV2-aPD1 showed comparable efficacy to the combination of unmodified HSV2 and PD-1 blockade.
• Local oHSV2-aPD1 treatment induced durable anti-tumor responses and activated immune cells and molecules.

Conclusions:

• Locally administered oHSV2-aPD1 is a potent therapeutic strategy for poorly immunogenic melanomas.
• This engineered oncolytic virus effectively combines oncolytic virotherapy with PD-1 blockade.
• The findings support further investigation of oncolytic viruses engineered to express immune checkpoint inhibitors for cancer therapy.