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CAR-Engineered NK Cells Targeting Wild-Type EGFR and EGFRvIII Enhance Killing of Glioblastoma and Patient-Derived Glioblastoma Stem Cells
- Source :
- Scientific Reports
- Publication Year :
- 2015
- Publisher :
- Springer Science and Business Media LLC, 2015.
-
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.
- Subjects :
- Cytotoxicity, Immunologic
Recombinant Fusion Proteins
medicine.medical_treatment
Receptors, Antigen, T-Cell
Gene Expression
Article
Interferon-gamma
Mice
ErbB Receptors
Antigen
Cancer immunotherapy
Cell Movement
Cell Line, Tumor
Animals
Humans
Medicine
Interferon gamma
Cytotoxicity
neoplasms
Multidisciplinary
business.industry
Wild type
Xenograft Model Antitumor Assays
nervous system diseases
Killer Cells, Natural
Disease Models, Animal
Cell culture
Immunology
Neoplastic Stem Cells
Cancer research
Stem cell
Glioblastoma
business
medicine.drug
Subjects
Details
- ISSN :
- 20452322
- Volume :
- 5
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....00bd48c5fdd88435942a29d36c456f8b