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; Jianhua Yu

doi:10.1038/s41467-021-26003-6

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

Nat Commun. 2021 Oct 8;12(1):5908. doi: 10.1038/s41467-021-26003-6.

Authors

Bo Xu^#¹, Lei Tian^#¹, Jing Chen^#², Jing Wang¹, Rui Ma¹, Wenjuan Dong¹, Aimin Li³, Jianying Zhang⁴, E Antonio Chiocca⁵, Balveen Kaur⁶, Mingye Feng², Michael A Caligiuri^{7

8

9}, Jianhua Yu^{10

11

12

13}

Affiliations

¹ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA.
² Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, CA, USA.
³ Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA.
⁴ Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, USA.
⁵ Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School, Boston, MA, USA.
⁶ The Vivian L. Smith Department of Neurosurgery, Mc Govern Medical School, University of Texas, University of Texas Health Science Center at Houston, Houston, TX, USA.
⁷ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. [email protected].
⁸ Comprenhensive Cancer Center, City of Hope, Los Angeles, CA, USA. [email protected].
⁹ Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. [email protected].
¹⁰ Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. [email protected].
¹¹ Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, CA, USA. [email protected].
¹² Comprenhensive Cancer Center, City of Hope, Los Angeles, CA, USA. [email protected].
¹³ Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. [email protected].

^# Contributed equally.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antibodies / immunology
Antibodies / pharmacology*
Antibody-Dependent Cell Cytotoxicity
CD47 Antigen
Disease Models, Animal
Female
Glioblastoma / immunology*
Glioblastoma / therapy*
Herpesvirus 1, Human / immunology
Humans
Immunity, Innate*
Immunoglobulin G
Immunotherapy
Killer Cells, Natural
Macrophages / immunology
Mice
Mice, Inbred C57BL
Mice, Nude
Oncolytic Virotherapy / methods
Oncolytic Viruses / immunology*
Phagocytosis
Tumor Microenvironment
Xenograft Model Antitumor Assays

Substances

Antibodies
CD47 Antigen
Cd47 protein, mouse
Immunoglobulin G

Abstract

Publication types

MeSH terms

Substances

Grants and funding