Purpose: To evaluate IL13Rα2 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 IL13Rα2-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 IL13Rα2 and for susceptibility to IL13-zetakine⁺ CTL-mediated killing in vitro and in vivo.

Results: We observed that although glioma IL13Rα2 expression varies between patients, for IL13Rα2^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 IL13Rα2^pos GSCs and IL13Rα2^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 IL13Rα2^pos GSC TS-initiated orthotopic tumors in mice.

Conclusions: Within IL13Rα2 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 IL13Rα2-directed immunotherapeutic approaches for eradicating therapeutically resistant GSC populations. Clin Cancer Res; 18(8); 2199–209. ©2012 AACR.