Research Papers:

A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases

Xilin Chen, Jianfeng Han, Jianhong Chu, Lingling Zhang, Jianying Zhang, Charlie Chen, Luxi Chen, Youwei Wang, Hongwei Wang, Long Yi, J. Bradley Elder, Qi-En Wang, Xiaoming He, Balveen Kaur, E. Antonio Chiocca and Jianhua Yu _

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Oncotarget. 2016; 7:27764-27777. https://doi.org/10.18632/oncotarget.8526

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Xilin Chen1,2,*, Jianfeng Han3,*, Jianhong Chu3,4,*, Lingling Zhang3,*, Jianying Zhang5, Charlie Chen3, Luxi Chen3, Youwei Wang3, Hongwei Wang3, Long Yi3, J. Bradley Elder3,8, Qi-En Wang6, Xiaoming He7, Balveen Kaur3,8, E. Antonio Chiocca9, Jianhua Yu1,3,10

1Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, Ohio 43210, USA

2Lymphoma/Head and Neck Oncology Department, 307 Hospital, Beijing 100071, China

3The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA

4Institute of Blood and Marrow Transplantation, Soochow University, Suzhou 215000, China

5Center for Biostatistics, The Ohio State University, Columbus, Ohio 43210, USA

6Department of Radiology, The Ohio State University, Columbus, Ohio 43210, USA

7Department of Biomedical Engineering, The Ohio State University, Columbus, Ohio 43210, USA

8Department of Neurological Surgery, The Ohio State University, Columbus, Ohio 43210, USA

9Department of Neurosurgery, Brigham and Women’s Hospital and Harvey Cushing Neuro-oncology Laboratories, Harvard Medical School, Boston, Massachusetts 02115, USA

10The James Cancer Hospital, Columbus, OH 43210, USA

*These authors have contributed equally to this work

Correspondence to:

Jianhua Yu, e-mail: [email protected]

Keywords: breast cancer brain metastases, chimeric antigen receptor, natural killer cells, EGFR, oncolytic virus

Received: October 13, 2015     Accepted: March 16, 2016     Published: April 01, 2016


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.

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