Adoptive Transfer of IL13R?2-Specific Chimeric Antigen Receptor T Cells Creates a Pro-inflammatory Environment in Glioblastoma.

ABSTRACT: In order to fully harness the potential of immunotherapy with chimeric antigen receptor (CAR)-modified T cells, pre-clinical studies must be conducted in immunocompetent animal models that closely mimic the immunosuppressive malignant glioma (MG) microenvironment. Thus, the goal of this project was to study the in vivo fate of T cells expressing CARs specific for the MG antigen IL13R?2 (IL13R?2-CARs) in immunocompetent MG models. Murine T cells expressing IL13R?2-CARs with a CD28.? (IL13R?2-CAR.CD28.?) or truncated signaling domain (IL13R?2-CAR.?) were generated by retroviral transduction, and their effector function was evaluated both in vitro and in vivo. IL13R?2-CAR.CD28.? T cells' specificity toward IL13R?2 was confirmed through cytokine production and cytolytic activity. In vivo, a single intratumoral injection of IL13R?2-CAR.CD28.? T cells significantly extended the survival of IL13R?2-expressing GL261 and SMA560 glioma-bearing mice; long-term survivors were resistant to re-challenge with IL13R?2-negative and IL13R?2-positive tumors. IL13R?2-CAR.CD28.? T cells proliferated, produced cytokines (IFN?, TNF-?), and promoted a phenotypically pro-inflammatory glioma microenvironment by inducing a significant increase in the number of CD4⁺ and CD8⁺ T cells and CD8?⁺ dendritic cells and a decrease in Ly6G⁺ myeloid-derived suppressor cells (MDSCs). Our data underline the significance of CAR T cell studies in immunocompetent hosts and further validate IL13R?2-CAR T cells as an efficacious therapeutic strategy for MG.

SUBMITTER: Pituch KC 

PROVIDER: S-EPMC6079480 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature