Suppression of Human Glioma Xenografts with Second-Generation IL13R-Specific Chimeric Antigen Receptor-Modified T Cells

Purpose: Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) designer T cell (dTc) immunotherapeutic strategy by exploiting interleukin (IL) 13 receptor alpha-2 (IL13R alpha 2) as a GBM-selective target. Experimental Design: We tested a second-generation IL13 zetakine CAR composed of a mutated IL13 extracellular domain linked to intracellular signaling elements of the CD28 costimulatory molecule and CD3 zeta. The aim of the mutation (IL13.E13K.R109K) was to enhance selectivity of the CAR for recognition and killing of IL13R alpha 2(+) GBMs while sparing normal cells bearing the composite IL13R alpha 1/IL4R alpha receptor. Results: Our aim was partially realized with improved recognition of tumor and reduced but persisting activity against normal tissue IL13R alpha 1(+) cells by the IL13.E13K.R109K CAR. We show that these IL13 dTcs were efficient in killing IL13R alpha 2(+) glioma cell targets with abundant secretion of cytokines IL2 and IFN gamma, and they displayed enhanced tumor-induced expansion versus control unmodified T cells in vitro. In an in vivo test with a human glioma xenograft model, single intracranial injections of IL13 dTc into tumor sites resulted in marked increases in animal survivals. Conclusions: These data raise the possibility of immune targeting of diffusely invasive GBM cells either via dTc infusion into resection cavities to prevent GBM recurrence or via direct stereotactic injection of dTcs to suppress inoperable or recurrent tumors. Systemic administration of these IL13 dTc could be complicated by reaction against normal tissues expressing IL13Ra1. Clin Cancer Res; 18(21); 5949-60. (C) 2012 AACR.