An oncolytic virus expressing a full-length antibody enhances antitumor innate immune response to glioblastoma

Oncolytic herpes simplex virus-1 lyses cancer cells while increases their immunogenicity. Blocking the CD47 don't eat me signal on cancer cells promotes their phagocytosis by macrophages. Authors here show that oncolytic viruses expressing anti-CD47 antibodies improve glioblastoma survival in mouse models. Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRP alpha, represents an important immune checkpoint to inhibit phagocytosis by innate immune cells. Here we show locoregional control of glioblastoma by an oncolytic herpes virus expressing a full-length anti(alpha)-human CD47 IgG1 or IgG4 antibody. The antibodies secreted by the virus-infected glioblastoma cells block the CD47 'don't eat me' signal irrespective of the subclass; however, alpha CD47-IgG1 has a stronger tumor killing effect than alpha CD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected alpha CD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, alpha CD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical alpha CD47-IgG1. Results from immunocompetent mouse tumor models further confirm that macrophages, and to a lesser extent NK cells, mediate the anti-tumor cytotoxicity of antibody-producing oncolytic herpesviruses. Collectively, oncolytic herpes simplex virus-1 encoding full-length antibodies could improve immune-virotherapy for glioblastoma.

Automated summary

Oncolytic herpes simplex virus-1 can lyse tumor cells and activate the immune system; oncolytic viruses expressing anti-CD47 antibodies can improve the survival of glioblastoma patients.