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

Bo Xu, Lei Tian, Jing Chen, Jing Wang, Rui Ma, Wenjuan Dong, Aimin Li, Jianying Zhang, E. Antonio Chiocca, Balveen Kaur, Mingye Feng, Michael A. Caligiuri () and Jianhua Yu ()
Additional contact information
Bo Xu: City of Hope National Medical Center
Lei Tian: City of Hope National Medical Center
Jing Chen: City of Hope Comprehensive Cancer Centre
Jing Wang: City of Hope National Medical Center
Rui Ma: City of Hope National Medical Center
Wenjuan Dong: City of Hope National Medical Center
Aimin Li: City of Hope National Medical Center
Jianying Zhang: City of Hope National Medical Center
E. Antonio Chiocca: Brigham and Women’s Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School
Balveen Kaur: University of Texas, University of Texas Health Science Center at Houston
Mingye Feng: City of Hope Comprehensive Cancer Centre
Michael A. Caligiuri: City of Hope National Medical Center
Jianhua Yu: City of Hope National Medical Center

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: Abstract Oncolytic herpes simplex virus-1 is capable of lysing tumor cells while alerting the immune system. CD47, in collaboration with SIRPα, 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(α)-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, αCD47-IgG1 has a stronger tumor killing effect than αCD47-IgG4 due to additional antibody-dependent cellular phagocytosis by macrophages and antibody-dependent cellular cytotoxicity by NK cells. Intracranially injected αCD47-IgG1-producing virus continuously releases the respective antibody in the tumor microenvironment but not into systemic circulation; additionally, αCD47-IgG1-producing virus also improves the survival of tumor-bearing mice better than control oncolytic herpes virus combined with topical αCD47-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.

Date: 2021
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DOI: 10.1038/s41467-021-26003-6

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