Human EGFRvIII chimeric antigen receptor T cells demonstrate favorable safety profile and curative responses in orthotopic glioblastoma
- Author(s)
- Abbott, RC; Iliopoulos, M; Watson, KA; Arcucci, V; Go, M; Hughes-Parry, HE; Smith, P; Call, MJ; Cross, RS; Jenkins, MR;
- Details
- Publication Year 2023,Volume 12,Issue #3,Page e1440
- Journal Title
- Clinical & Translational Immunology
- Abstract
- OBJECTIVES: Glioblastoma is a highly aggressive and fatal brain malignancy, and effective targeted therapies are required. The combination of standard treatments including surgery, chemotherapy and radiotherapy is not curative. Chimeric antigen receptor (CAR) T cells are known to cross the blood-brain barrier, mediating antitumor responses. A tumor-expressed deletion mutant of the epidermal growth factor receptor (EGFRvIII) is a robust CAR T cell target in glioblastoma. Here, we show our de novo generated, high-affinity EGFRvIII-specific CAR; GCT02, demonstrating curative efficacy in human orthotopic glioblastoma models. METHODS: The GCT02 binding epitope was predicted using Deep Mutational Scanning (DMS). GCT02 CAR T cell cytotoxicity was investigated in three glioblastoma models in vitro using the IncuCyte platform, and cytokine secretion with a cytometric bead array. GCT02 in vivo functionality was demonstrated in two NSG orthotopic glioblastoma models. The specificity profile was generated by measuring T cell degranulation in response to coculture with primary human healthy cells. RESULTS: The GCT02 binding location was predicted to be located at a shared region of EGFR and EGFRvIII; however, the in vitro functionality remained exquisitely EGFRvIII specific. A single CAR T cell infusion generated curative responses in two orthotopic models of human glioblastoma in NSG mice. The safety analysis further validated the specificity of GCT02 for mutant-expressing cells. CONCLUSION: This study demonstrates the preclinical functionality of a highly specific CAR targeting EGFRvIII on human cells. This CAR could be an effective treatment for glioblastoma and warrants future clinical investigation.
- Publisher
- Wiley
- Keywords
- CAR T cells; EGFRvIII; chimeric antigen receptor; glioblastoma; immunotherapy
- Research Division(s)
- Immunology; Structural Biology
- PubMed ID
- 36890859
- Publisher's Version
- https://doi.org/10.1002/cti2.1440
- Open Access at Publisher's Site
https://doi.org/10.1002/cti2.1440- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2023-03-29 08:33:55
Last Modified: 2023-03-29 08:39:44