Characterization and Functional Analysis of scFv-based Chimeric Antigen Receptors to Redirect T Cells to IL13R?2-positive Glioma.

ABSTRACT: Immunotherapy with T cells expressing chimeric antigen receptors (CARs) is an attractive approach to improve outcomes for patients with glioblastoma (GBM). IL13R?2 is expressed at a high frequency in GBM but not in normal brain, making it a promising CAR T-cell therapy target. IL13R?2-specific CARs generated up to date contain mutated forms of IL13 as an antigen-binding domain. While these CARs target IL13R?2, they also recognize IL13R?1, which is broadly expressed. To overcome this limitation, we constructed a panel of IL13R?2-specific CARs that contain the IL13R?2-specific single-chain variable fragment (scFv) 47 as an antigen binding domain, short or long spacer regions, a transmembrane domain, and endodomains derived from costimulatory molecules and CD3.? (IL13R?2-CARs). IL13R?2-CAR T cells recognized IL13R?2-positive target cells in coculture and cytotoxicity assays with no cross-reactivity to IL13R?1. However, only IL13R?2-CAR T cells with a short spacer region produced IL2 in an antigen-dependent fashion. In vivo, T cells expressing IL13R?2-CARs with short spacer regions and CD28.?, 41BB.?, and CD28.OX40.? endodomains had potent anti-glioma activity conferring a significant survival advantage in comparison to mice that received control T cells. Thus, IL13R?2-CAR T cells hold the promise to improve current IL13R?2-targeted immunotherapy approaches for GBM and other IL13R?2-positive malignancies.

SUBMITTER: Krenciute G 

PROVIDER: S-EPMC4817815 | biostudies-other | 2016 Feb

REPOSITORIES: biostudies-other