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.
Highlights
Are a promising alternative to conventional treatments with a potential long-term benefit of generating a sustainable anti-tumor response with potential to target both localized and infiltrating tumor cells[3]
To further address whether wild-type epidermal growth factor receptor (EGFR) (wtEGFR) or EGFRvIII transcript was expressed in these cells, we carried out RT-PCR with specific primers and observed that wtEGFR mRNA was expressed in two GB cell lines, U251 and LN229
EGFRvIII mRNA was detectable in the GB cell line Gli36dEGFR, and in GB stem cells (GSCs) generated from six GB patients[16]: GB30, GB83, GB1123, GB326, GB84V3SL and GB157V3SL (Fig. 1B)
Summary
Are a promising alternative to conventional treatments with a potential long-term benefit of generating a sustainable anti-tumor response with potential to target both localized and infiltrating tumor cells[3]. 20–40% of EGFR-amplified tumors harbor the EGFR variant III mutant (EGFRvIII), which contains a deletion of exons 2–7 in the extracellular ligand-binding domain[7,8,9,10]. This mutant form shows constitutive activation in the absence of ligand to activate the tumor-promoting signaling pathways[11]. These studies suggest that targeting both wtEGFR and EGFRvIII could be important for effective treatment of GB. We evaluated the anti-GB capacity of human NK cell lines including NK-92 and NKL and primary NK cells engineered to express an EGFR-specific CAR targeting both wtEGFR and EGFRvIII, and demonstrated the feasibility and efficacy of EGFR-CAR-armed NK cells against GB
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
