To improve oncolytic viral therapy for glioblastoma (GBM) and other solid tumors, Tian and Xu et al. constructed OV-Cmab-CCL5, an HSV type 1-derived oncolytic virus secreting a heterodimeric Fc-based fusion protein with an scFv that targeted EGFR (both wt and mutant vIII) and active CCL5, allowing continuous high secretion of CCL5 in the EGFR+ GBM TME. Intratumoral OV-Cmab-CCL5 infection of GBM in murine tumor models resulted in direct tumor lysis; inhibition of EGFR signaling; significantly increased migration and activation of NK cells, macrophages and T cells; and decreased tumor size and prolonged survival.
Contributed by Katherine Turner
ABSTRACT: Chemokines such as C-C motif ligand 5 (CCL5) regulate immune cell trafficking in the tumor microenvironment (TME) and govern tumor development, making them promising targets for cancer therapy. However, short half-lives and toxic off-target effects limit their application. Oncolytic viruses (OVs) have become attractive therapeutic agents. Here, we generate an oncolytic herpes simplex virus type 1 (oHSV) expressing a secretable single-chain variable fragment of the epidermal growth factor receptor (EGFR) antibody cetuximab linked to CCL5 by an Fc knob-into-hole strategy that produces heterodimers (OV-Cmab-CCL5). OV-Cmab-CCL5 permits continuous production of CCL5 in the TME, as it is redirected to EGFR(+) glioblastoma (GBM) tumor cells. OV-Cmab-CCL5 infection of GBM significantly enhances the migration and activation of natural killer cells, macrophages and T cells; inhibits tumor EGFR signaling; reduces tumor size; and prolongs survival of GBM-bearing mice. Collectively, our data demonstrate that OV-Cmab-CCL5 offers a promising approach to improve OV therapy for solid tumors.
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 Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 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 Computational and Quantitative Medicine, City of Hope National Medical Center, Los Angeles, CA, USA. (7) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (8) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, Los Angeles, CA, USA. (9) Department of Immunology and Theranostics, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Los Angeles, CA, USA. (10) Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neurooncology Laboratories, Harvard Medical School, Boston, MA, USA. (11) Georgia Cancer Center, Augusta University Medical Center, Augusta, GA, USA. (12) Department of Hematology and Hematopoietic Cell Transplantation, City of Hope National Medical Center, 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. Hematologic Malignancies Research Institute, 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 Center, Los Angeles, CA, USA. jiayu@coh.org.
