By engineering an oncolytic virus (OV) to express αCD47, Xu et al. combined OV and ICB into a single therapeutic agent designed to attack tumors by both oncolysis and blockade of the anti-phagocytic CD47–SIRPα “don’t eat me” checkpoint. In glioblastoma models, intracranial delivery of OV expressing αCD47 of the IgG1 isotype led to direct tumor lysis, innate immune cell infiltration and activation in the TME, blockade of the CD47/SIRPα checkpoint, αCD47-mediated ADCP via bridging of Fcγ receptors to CD47 on tumor cells, and NK-mediated ADCC. Among αCD47-expressing OV, Fc binding-deficient IgG4 was less effective against tumors than IgG1.
Contributed by Margot O’Toole
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.
Author Info: (1) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (2) Department of Hematology and Hematopoietic Cell
Author Info: (1) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (2) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (3) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, CA, USA. (4) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (5) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (6) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (7) Pathology Core of Shared Resources Core, Beckman Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. (8) Department of Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, USA. (9) Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School, Boston, MA, USA. (10) 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. (11) Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, CA, USA. (12) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. mcaligiuri@coh.org. Comprenhensive Cancer Center, City of Hope, Los Angeles, CA, USA. mcaligiuri@coh.org. Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. mcaligiuri@coh.org. (13) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. jiayu@coh.org. Department of Immuno-Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Centre, Los Angeles, CA, USA. jiayu@coh.org. Comprenhensive Cancer Center, City of Hope, Los Angeles, CA, USA. jiayu@coh.org. Hematologic Malignancies Research Institute, City of Hope National Medical Center, Los Angeles, CA, USA. jiayu@coh.org.
