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

Abstract

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.

• Authors: Christine E Brown, Brenda Aguilar, Renate Starr, Xin Yang, Wen-Chung Chang, Lihong Weng, Brenda Chang, Aniee Sarkissian, Alfonso Brito, James F Sanchez, Julie R Ostberg, Massimo D'Apuzzo, Behnam Badie, Michael E Barish, Stephen J Forman
• Journal: Molecular therapy : the journal of the American Society of Gene Therapy (Mol Ther) Vol. 26 Issue 1 Pg. 31-44 (01 03 2018) ISSN: 1525-0024 [Electronic] United States
• PMID: 29103912 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2017 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.

Chemical References

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

Topics

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