title: A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases.
abstract: Breast cancer brain metastases (BCBMs) are common in patients with metastatic breast cancer and indicate a poor prognosis. These tumors are especially resistant to currently available treatments due to multiple factors. However, the combination of chimeric antigen receptor (CAR)-modified immune cells and oncolytic herpes simplex virus (oHSV) has not yet been explored in this context. In this study, NK-92 cells and primary NK cells were engineered to express the second generation of EGFR-CAR. The efficacies of anti-BCBMs of EGFR-CAR NK cells, oHSV-1, and their combination were tested in vitro and in a breast cancer intracranial mouse model. In vitro, compared with mock-transduced NK-92 cells or primary NK cells, EGFR-CAR-engineered NK-92 cells and primary NK cells displayed enhanced cytotoxicity and IFN-γ production when co-cultured with breast cancer cell lines MDA-MB-231, MDA-MB-468, and MCF-7. oHSV-1 alone was also capable of lysing and destroying these cells. However, a higher cytolytic effect of EGFR-CAR NK-92 cells was observed when combined with oHSV-1 compared to the monotherapies. In the mice intracranially pre-inoculated with EGFR-expressing MDA-MB-231 cells, intratumoral administration of either EGFR-CAR-transduced NK-92 cells or oHSV-1 mitigated tumor growth. Notably, the combination of EGFR-CAR NK-92 cells with oHSV-1 resulted in more efficient killing of MDA-MB-231 tumor cells and significantly longer survival of tumor-bearing mice when compared to monotherapies. These results demonstrate that regional administration of EGFR-CAR NK-92 cells combined with oHSV-1 therapy is a potentially promising strategy to treat BCBMs.
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.|Lymphoma/Head and Neck Oncology Department, 307 Hospital, Beijing 100071, China.
authors.forename: Xilin
authors.initials: X
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Han
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.|Institute of Blood and Marrow Transplantation, Soochow University, Suzhou 215000, China.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Chu
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Lingling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Jianying
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Charlie
authors.initials: C
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Luxi
authors.initials: L
authors.lastname: Chen
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Youwei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
authors.forename: Long
authors.initials: L
authors.lastname: Yi
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.|Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: J Bradley
authors.initials: JB
authors.lastname: Elder
authors.affiliation: Department of Radiology, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
authors.affiliation: Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: He
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.|Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Balveen
authors.initials: B
authors.lastname: Kaur
authors.affiliation: Department of Neurosurgery, Brigham and Women's Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: E Antonio
authors.initials: EA
authors.lastname: Chiocca
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA.|The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.|The James Cancer Hospital, Columbus, OH 43210, USA.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Yu
mesh_terms: D000818:Animals; D001921:Brain; D001932:Brain Neoplasms / Q000473:pathology / Q000556:secondary / Q000628:therapy*; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D060846:Cell Engineering; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D003131:Combined Modality Therapy; D003602:Cytotoxicity, Immunologic; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005909:Glioblastoma / Q000556:secondary / Q000628:therapy*; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D061986:MCF-7 Cells; D051379:Mice; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses; D011946:Receptors, Antigen / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D011946:Receptors, Antigen; D007371:Interferon-gamma; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; breast cancer brain metastases; chimeric antigen receptor; natural killer cells; oncolytic virus