Stem-like Tumor-Initiating Cells Isolated from IL13Rα2 Expressing Gliomas Are Targeted and Killed by IL13-Zetakine-Redirected T Cells

Purpose: To evaluate IL13R alpha 2 as an immunotherapeutic target for eliminating glioma stem-like cancer initiating cells (GSC) of high-grade gliomas, with particular focus on the potential of genetically engineered IL13R alpha 2-specific primary human CD8(+) CTLs (IL13-zetakine(+) CTL) to target this therapeutically resistant glioma subpopulation. Experimental Design: A panel of low-passage GSC tumor sphere (TS) and serum-differentiated glioma lines were expanded from patient glioblastoma specimens. These glioblastoma lines were evaluated for expression of IL13R alpha 2 and for susceptibility to IL13-zetakine(+) CTL-mediated killing in vitro and in vivo. Results: We observed that although glioma IL13R alpha 2 expression varies between patients, for IL13R alpha 2(pos) cases this antigen was detected on both GSCs and more differentiated tumor cell populations. IL13-zetakine(+) CTL were capable of efficient recognition and killing of both IL13R alpha 2(pos) GSCs and IL13R alpha 2(pos) differentiated cells in vitro, as well as eliminating glioma-initiating activity in an orthotopic mouse tumor model. Furthermore, intracranial administration of IL13-zetakine(+) CTL displayed robust antitumor activity against established IL13R alpha 2(pos) GSC TS-initiated orthotopic tumors in mice. Conclusions: Within IL13R alpha 2 expressing high-grade gliomas, this receptor is expressed by GSCs and differentiated tumor populations, rendering both targetable by IL13-zetakine(+) CTLs. Thus, our results support the potential usefullness of IL13R alpha 2-directed immunotherapeutic approaches for eradicating therapeutically resistant GSC populations. Clin Cancer Res; 18(8); 2199-209. (C) 2012 AACR.