Han, JianfengChu, JianhongKeung Chan, WingZhang, JianyingWang, YouweiCohen, Justus B.Victor, AaronMeisen, Walter H.Kim, Sung-hakGrandi, PaolaWang, Qi-EnHe, XiaomingNakano, IchiroChiocca, E.Glorioso III, Joseph C.Kaur, BalveenCaligiuri, Michael A.Yu, Jianhua2015-08-032015Han, J., J. Chu, W. Keung Chan, J. Zhang, Y. Wang, J. B. Cohen, A. Victor, et al. 2015. “CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells.” Scientific Reports 5 (1): 11483. doi:10.1038/srep11483. http://dx.doi.org/10.1038/srep11483.2045-2322http://nrs.harvard.edu/urn-3:HUL.InstRepos:17820801Glioblastoma (GB) remains the most aggressive primary brain malignancy. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered natural killer (NK) cells to treat GB has not been explored. Tumors from approximately 50% of GB patients express wild-type EGFR (wtEGFR) and in fewer cases express both wtEGFR and the mutant form EGFRvIII; however, previously reported CAR T cell studies only focus on targeting EGFRvIII. Here we explore whether both wtEGFR and EGFRvIII can be effectively targeted by CAR-redirected NK cells to treat GB. We transduced human NK cell lines NK-92 and NKL, and primary NK cells with a lentiviral construct harboring a second generation CAR targeting both wtEGFR and EGFRvIII and evaluated the anti-GB efficacy of EGFR-CAR-modified NK cells. EGFR-CAR-engineered NK cells displayed enhanced cytolytic capability and IFN-γ production when co-cultured with GB cells or patient-derived GB stem cells in an EGFR-dependent manner. In two orthotopic GB xenograft mouse models, intracranial administration of NK-92-EGFR-CAR cells resulted in efficient suppression of tumor growth and significantly prolonged the tumor-bearing mice survival. These findings support intracranial administration of NK-92-EGFR-CAR cells represents a promising clinical strategy to treat GB.en-USJournal Article2015-08-0310.1038/srep11483