IL-13Rα2-Targeted Therapy Escapees: Biologic and Therapeutic Implications

Abstract

Glioblastoma multiforme (GBM) overexpresses interleukin 13 receptor α2 (IL-13Rα2), a tumor-restricted receptor that is not present in normal brain. We and others have created targeted therapies that specifically eradicate tumors expressing this promising tumor-restricted biomarker. As these therapies head toward clinical implementation, it is critical to explore mechanisms of potential resistance. We therefore used a potent IL-13Rα2-targeted bacterial cytotoxin to select for naturally occurring "escapee" cells from three different IL-13Rα2-expressing GBM cell lines. We found that these side populations of escapee cells had significantly decreased IL-13Rα2 expression. We examined clinically relevant biologic characteristics of escapee cell lines compared to their parental cell lines and found that they had similar proliferation rates and equal sensitivity to temozolomide and radiation, the standard therapies given to GBM patients. In contrast, our escapee cell lines were less likely to form colonies in culture and migrated more slowly in wound healing assays. Furthermore, we found that escapee cells formed significantly less neurospheres in vitro, suggesting that IL-13Rα2-targeted therapy preferentially targeted the "stem-like" cell population and possibly indicating decreased tumorigenicity in vivo. We therefore tested escapee cells for in vivo tumorigenicity and found that they were significantly less tumorigenic in both subcutaneous and intracranial mouse models compared to matching parental cells. These data, for the first time, establish and characterize the clinically relevant biologic properties of IL-13Rα2-targeted therapy escapees and suggest that these cells may have less malignant characteristics than parental tumors.

T cells redirected to interleukin-13Rα2 with interleukin-13 mutein–chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1

“…IL13Rα2 is a promising immunotherapy target for GBM [25]. The receptor has been targeted with immunotoxins, vaccines, and antigen-specific T cells with encouraging results [8, 11, 26-28].…”

Targeting of IL-4 and IL-13 receptors for cancer therapy

“…Similarly, IL-13 receptors (IL-13Rs) are over expressed in a variety of human solid cancers [19][20][21][22]. In addition, IL-4 and IL-13 have been shown to be key regulatory cytokines in the tumor microenvironment and activate tumor-associated macrophages and myeloid-derived suppressor cells ( pro-tumor activity [23][24][25].…”

New Agents for Targeting of IL-13RA2 Expressed in Primary Human and Canine Brain Tumors

“…The current study demonstrates that it is also a valid target in a clinically relevant spontaneous animal model of human disease, namely spontaneously occurring canine brain tumors. The IL-13RA2 receptor belongs to a tri-molecular signature of human GBM also including the EphA2 receptor and a transcription factor Fra-1 (19), and recent studies are suggestive of IL-13RA2 and EphA2 belonging to a group of factors characterizing glioma stem-like cells [38-40]. The availability of specific and sensitive antibodies recognizing the receptor under various conditions will be important in further studies examining the pathophysiological role of IL-13RA2 in brain tumors, including its closest translational model in a form of spontaneous canine tumors.…”