T cells redirected to EphA2 for the immunotherapy of glioblastoma

Kevin KH Chow, Swati Naik, Sunitha Kakarla, Vita S. Brawley, Donald R. Shaffer, Zhongzhen Yi, Nino Rainusso, Meng Fen Wu, Hao Liu, Yvonne Kew, Robert G. Grossman, Suzanne Powell, Dean Lee, Nabil Ahmed, Stephen Gottschalk

Research output: Contribution to journalArticle

124 Scopus citations

Abstract

Outcomes for patients with glioblastoma (GBM) remain poor despite aggressive multimodal therapy. Immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) targeting interleukin (IL)-13Rα2, epidermal growth factor receptor variant III (EGFRvIII), or human epidermal growth factor receptor 2 (HER2) has shown promise for the treatment of gliomas in preclinical models and in a clinical study (IL-13Rα2). However, targeting IL-13Rα2 and EGFRvIII is associated with the development of antigen loss variants, and there are safety concerns with targeting HER2. Erythropoietin-producing hepatocellular carcinoma A2 (EphA2) has emerged as an attractive target for the immunotherapy of GBM as it is overexpressed in glioma and promotes its malignant phenotype. To generate EphA2-specific T cells, we constructed an EphA2-specific CAR with a CD28-ζ endodomain. EphA2-specific T cells recognized EphA2-positive glioma cells as judged by interferon-γ (IFN-γ) and IL-2 production and tumor cell killing. In addition, EphA2-specific T cells had potent activity against human glioma-initiating cells preventing neurosphere formation and destroying intact neurospheres in coculture assays. Adoptive transfer of EphA2-specific T cells resulted in the regression of glioma xenografts in severe combined immunodeficiency (SCID) mice and a significant survival advantage in comparison to untreated mice and mice treated with nontransduced T cells. Thus, EphA2-specific T-cell immunotherapy may be a promising approach for the treatment of EphA2-positive GBM.

Original languageEnglish (US)
Pages (from-to)629-637
Number of pages9
JournalMolecular Therapy
Volume21
Issue number3
DOIs
StatePublished - Mar 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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  • Cite this

    Chow, K. KH., Naik, S., Kakarla, S., Brawley, V. S., Shaffer, D. R., Yi, Z., Rainusso, N., Wu, M. F., Liu, H., Kew, Y., Grossman, R. G., Powell, S., Lee, D., Ahmed, N., & Gottschalk, S. (2013). T cells redirected to EphA2 for the immunotherapy of glioblastoma. Molecular Therapy, 21(3), 629-637. https://doi.org/10.1038/mt.2012.210