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

Brown, Christine E. ; Aguilar, Brenda ; Starr, Renate ; Yang, Xin ; Chang, Wen-Chung ; Weng, Lihong ; Chang, Brenda ; Sarkissian, Aniee ; Brito, Alfonso ; Sanchez, James F. ; Ostberg, Julie R. ; D’Apuzzo, Massimo ; Badie, Behnam ; Barish, Michael E. ; Forman, Stephen J.

Molecular therapy, 2018-01, Vol.26 (1), p.31-44 [Periódico revisado por pares]

United States: Elsevier Inc

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Título:
Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma
Autor: Brown, Christine E. ; Aguilar, Brenda ; Starr, Renate ; Yang, Xin ; Chang, Wen-Chung ; Weng, Lihong ; Chang, Brenda ; Sarkissian, Aniee ; Brito, Alfonso ; Sanchez, James F. ; Ostberg, Julie R. ; D’Apuzzo, Massimo ; Badie, Behnam ; Barish, Michael E. ; Forman, Stephen J.
Assuntos: adoptive cellular immunotherapy ; Animal models ; Animals ; Antibodies, Neoplasm - immunology ; Antigens ; Antigens, CD19 - immunology ; Antitumor agents ; Biological activity ; Brain cancer ; Brain Neoplasms - immunology ; Brain Neoplasms - metabolism ; Brain Neoplasms - therapy ; Brain tumors ; Cancer ; CD137 antigen ; CD8 antigen ; chimeric antigen receptor ; Chimeric antigen receptors ; Corticosteroids ; Cytotoxicity, Immunologic ; Dexamethasone ; Dextroamphetamine - pharmacology ; Disease Models, Animal ; Gene Order ; Genetic Engineering ; Genetic Vectors - genetics ; Glioblastoma ; Glioblastoma - immunology ; Glioblastoma - metabolism ; Glioblastoma - mortality ; Glioblastoma - therapy ; Humans ; Immunological memory ; Immunotherapy ; Immunotherapy, Adoptive - methods ; Interleukin 1 ; Interleukin 13 ; Interleukin-13 Receptor alpha2 Subunit - antagonists & inhibitors ; Interleukin-13 Receptor alpha2 Subunit - immunology ; Intravenous administration ; Ligands ; Lymphocytes ; Lymphocytes T ; Memory cells ; Metastasis ; Mice ; Original ; Patients ; Receptors, Chimeric Antigen - chemistry ; Receptors, Chimeric Antigen - metabolism ; Software ; T-Lymphocytes - immunology ; T-Lymphocytes - metabolism ; Tumors ; Xenograft Model Antitumor Assays
É parte de: Molecular therapy, 2018-01, Vol.26 (1), p.31-44
Notas: ObjectType-Article-1
SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: United States: Elsevier Inc
Idioma: Inglês

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

Brown, Christine E. ; Aguilar, Brenda ; Starr, Renate ; Yang, Xin ; Chang, Wen-Chung ; Weng, Lihong ; Chang, Brenda ; Sarkissian, Aniee ; Brito, Alfonso ; Sanchez, James F. ; Ostberg, Julie R. ; D’Apuzzo, Massimo ; Badie, Behnam ; Barish, Michael E. ; Forman, Stephen J.

United States: Elsevier Inc

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