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

摘要

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. In this issue of Molecular Therapy , Brown et?al. (2017) actively explore the use of optimized, second-generation IL13Rα2-targeted CAR T?cells to treat glioblastoma. The results provide important insights into parameters impacting the translation of CAR T?cells for malignant brain tumors.