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

Sci Rep. 2015 Jul 9;5:11483. doi: 10.1038/srep11483.

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.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Cell Movement / immunology
  • Cytotoxicity, Immunologic*
  • Disease Models, Animal
  • ErbB Receptors / genetics
  • ErbB Receptors / immunology*
  • ErbB Receptors / metabolism
  • Gene Expression
  • Glioblastoma / genetics*
  • Glioblastoma / immunology*
  • Glioblastoma / pathology
  • Humans
  • Interferon-gamma / biosynthesis
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism*
  • Mice
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / metabolism
  • Receptors, Antigen, T-Cell / genetics*
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / immunology
  • Xenograft Model Antitumor Assays

Substances

  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins
  • epidermal growth factor receptor VIII
  • Interferon-gamma
  • ErbB Receptors