CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells

Abstract

Glioblastoma (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.

NK cells and cancer: you can teach innate cells new tricks

“…160) and G D2 (REF. 161) showed increased responses to tumour cells in vitro and suppressed tumour growth when tested in vivo in xenograft models 162,163 . Although initially considered as receptors providing 'built-in' ADCC-like NCRL activity against specific tumour antigens, CARs actually elicit a significantly stronger NK cell cytotoxic response than ADCC mediated by anti bodies against the same targets 164 .…”

NK Cells in Cancer Immunotherapy

“…In human multiple myeloma (MM), CS1-speciic (a surface protein highly expressed on MM cells) chimeric antigen receptor (CAR)-engineered natural killer cells [79] enhance responses to tumor cells in vitro and suppressed tumor growth when tested in vivo in xenograft models [65,78,80]. Autologous or allogeneic transplantation of CS1-speciic CAR NK cells may be a promising strategy to treat multiple myeloma.…”

“…In glioblastoma, the most aggressive primary brain malignancy, intracranial administration of NK-92-EGFR-CAR cells represents a promising therapy [78]. In human multiple myeloma (MM), CS1-speciic (a surface protein highly expressed on MM cells) chimeric antigen receptor (CAR)-engineered natural killer cells [79] enhance responses to tumor cells in vitro and suppressed tumor growth when tested in vivo in xenograft models [65,78,80].…”

Chimeric Antigen Receptor Therapeutic Strategies: The Future of Glioblastoma Management

“…Additionally, groups have explored the use of CAR-modified natural killer (NK) cells for treatment of GBM [29].…”