Arming HSV-Based Oncolytic Viruses with the Ability to Redirect the Host’s Innate Antiviral Immunity to Attack Tumor Cells

One of the major hurdles for cancer immunotherapy is the host’s innate antiviral defense mechanisms. They include innate immune cells, such as natural killer (NK) cells and macrophages, which can be recruited within hours to the site of injection to clear the introduced oncolytic viruses. Here, we report a strategy to redirect these infiltrating innate immune cells to attack tumor cells instead by arming herpes simplex virus (HSV)-derived oncolytic viruses with secreted chimeric molecules that can engage these innate immune cells with tumor cells to kill the latter. These chimeric molecules have, at their N terminus, a custom-binding moiety for a tumor-associated antigen (TAA) and at their C terminus, protein L (PL) that binds to immunoglobulins (Igs). The binding of PL to Igs exposes the Fc to the Fc receptors on the surface of the innate immune cells, trigging them to attack the engaged tumor cells. In vitro and in vivo evaluation in a murine tumor model with limited permissiveness to oncolytic HSVs showed that arming the viruses with these chimeric molecules significantly boosts the killing effect and therapeutic activity. Moreover, our data also showed that the combined killing effect from the engaged innate immune cells and the oncolytic virus resulted in a more efficient stimulation of neoantigen-specific antitumor immunity than the virotherapy alone. Our data suggest that arming an oncolytic virus with this strategy represents a unique and pragmatic way of potentiating the oncolytic and immunotherapeutic effect of virotherapy.