Journal for ImmunoTherapy of Cancer (Aug 2024)

EphA3-targeted chimeric antigen receptor T cells are effective in glioma and generate curative memory T cell responses

  • Katharine J Drummond,
  • Jordan R Hansford,
  • Misty R Jenkins,
  • Lisa M Ebert,
  • Leesa Lertsumitkul,
  • Melinda Iliopoulos,
  • Stacie S Wang,
  • Sarah J McArthur,
  • Alexander J Davenport,
  • Raelene Endersby,
  • Ryan Cross

DOI
https://doi.org/10.1136/jitc-2024-009486
Journal volume & issue
Vol. 12, no. 8

Abstract

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Background High-grade gliomas including glioblastoma (GBM) and diffuse midline gliomas (DMG) represent the most lethal and aggressive brain cancers where current treatment modalities offer limited efficacy. Chimeric antigen receptor (CAR) T cell therapies have emerged as a promising strategy, boasting tumor-specific targeting and the unique ability to penetrate the blood-brain barrier. However, the effective clinical application hinges on the optimal choice of antigen, with a limited number, currently under investigation.Methods We employed cell surface proteomic analysis of primary human high-grade glioma samples from both adult and pediatric patients. This led to the identification of Ephrin type-A receptor 3 (EphA3) as a prevalently expressed target. We engineered a second-generation EphA3-targeted CAR T cell and assessed function using in vitro and in vivo models of GBM and DMG.Results EphA3-targeted CAR T cells demonstrated robust antigen-specific killing of human GBM and DMG cell lines in vitro. In an orthotopic xenograft NSG mouse model, EphA3-targeted CAR T cells not only effectively eradicated tumors but also established a functional T cell population protective on rechallenge. Remarkably, mice rechallenged with a second contralateral orthotopic tumor implantation achieved complete tumor clearance and maintained a sustained complete response 6 months following initial treatment.Conclusion Building on the proven safety profile of EphA3 antibodies in clinical settings, our study provides compelling preclinical evidence supporting the efficacy of EphA3-targeted CAR T cells against high-grade gliomas. These findings underscore the potential for transitioning this innovative therapy into clinical trials, aiming to revolutionize the treatment landscape for patients afflicted with these formidable brain cancers.