Abstract | BACKGROUND AIMS: METHODS: We constructed four second-generation CARs with IL13 muteins with one or two amino acid substitutions, and evaluated the effector function of IL13-mutein CAR T cells in vitro and in vivo. RESULTS: T cells expressing all four CARs recognized IL13Rα1 or IL13Rα2 recombinant protein in contrast to control protein (IL4R) as judged by interferon-γ production. IL13 protein produced significantly more IL2, indicating that IL13 mutein-CAR T cells have a higher affinity to IL13Rα2 than to IL13Rα1. In cytotoxicity assays, CAR T cells killed IL13Rα1- and/or IL13Rα2-positive cells in contrast to IL13Rα1- and IL13Rα2-negative controls. Although we observed no significant differences between IL13 mutein-CAR T cells in vitro, only T cells expressing IL13 mutein-CARs with an E13K amino acid substitution had anti- tumor activity in vivo that resulted in a survival advantage of treated animals. CONCLUSIONS: Our study highlights that the specificity/avidity of ligands is context-dependent and that evaluating CAR T cells in preclinical animal model is critical to assess their potential benefit.
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Authors | Simone Krebs, Kevin K H Chow, Zhongzhen Yi, Tania Rodriguez-Cruz, Meenakshi Hegde, Claudia Gerken, Nabil Ahmed, Stephen Gottschalk |
Journal | Cytotherapy
(Cytotherapy)
Vol. 16
Issue 8
Pg. 1121-31
(Aug 2014)
ISSN: 1477-2566 [Electronic] England |
PMID | 24841514
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2014 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- Immunotoxins
- Interleukin-13 Receptor alpha1 Subunit
- Interleukin-13 Receptor alpha2 Subunit
- Receptors, Antigen, T-Cell
- Recombinant Proteins
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Topics |
- Amino Acid Substitution
- Animals
- Gene Expression Regulation, Neoplastic
(immunology)
- Glioblastoma
(immunology, pathology, therapy)
- Humans
- Immunotherapy
- Immunotoxins
(genetics)
- Interleukin-13 Receptor alpha1 Subunit
(genetics, immunology)
- Interleukin-13 Receptor alpha2 Subunit
(genetics, immunology)
- Mice
- Receptors, Antigen, T-Cell
(genetics, immunology)
- Recombinant Proteins
(genetics, immunology)
- T-Lymphocytes
(immunology)
- Xenograft Model Antitumor Assays
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