Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma

Mol Ther. 2018 Jan 3;26(1):31-44. doi: 10.1016/j.ymthe.2017.10.002. Epub 2017 Oct 5.


T cell immunotherapy is emerging as a powerful strategy to treat cancer and may improve outcomes for patients with glioblastoma (GBM). We have developed a chimeric antigen receptor (CAR) T cell immunotherapy targeting IL-13 receptor α2 (IL13Rα2) for the treatment of GBM. Here, we describe the optimization of IL13Rα2-targeted CAR T cells, including the design of a 4-1BB (CD137) co-stimulatory CAR (IL13BBζ) and a manufacturing platform using enriched central memory T cells. Utilizing orthotopic human GBM models with patient-derived tumor sphere lines in NSG mice, we found that IL13BBζ-CAR T cells improved anti-tumor activity and T cell persistence as compared to first-generation IL13ζ-CAR CD8+ T cells that had shown evidence for bioactivity in patients. Investigating the impact of corticosteroids, given their frequent use in the clinical management of GBM, we demonstrate that low-dose dexamethasone does not diminish CAR T cell anti-tumor activity in vivo. Furthermore, we found that local intracranial delivery of CAR T cells elicits superior anti-tumor efficacy as compared to intravenous administration, with intraventricular infusions exhibiting possible benefit over intracranial tumor infusions in a multifocal disease model. Overall, these findings help define parameters for the clinical translation of CAR T cell therapy for the treatment of brain tumors.

Keywords: adoptive cellular immunotherapy; chimeric antigen receptor; glioblastoma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antibodies, Neoplasm / immunology
  • Antigens, CD19 / immunology
  • Brain Neoplasms / immunology
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / therapy
  • Cytotoxicity, Immunologic
  • Dextroamphetamine / pharmacology
  • Disease Models, Animal
  • Gene Order
  • Genetic Engineering
  • Genetic Vectors / genetics
  • Glioblastoma / immunology*
  • Glioblastoma / metabolism*
  • Glioblastoma / mortality
  • Glioblastoma / therapy
  • Humans
  • Immunotherapy, Adoptive* / methods
  • Interleukin-13 Receptor alpha2 Subunit / antagonists & inhibitors*
  • Interleukin-13 Receptor alpha2 Subunit / immunology
  • Mice
  • Receptors, Chimeric Antigen / chemistry
  • Receptors, Chimeric Antigen / metabolism*
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism*
  • Xenograft Model Antitumor Assays


  • Antibodies, Neoplasm
  • Antigens, CD19
  • Interleukin-13 Receptor alpha2 Subunit
  • Receptors, Chimeric Antigen
  • Dextroamphetamine