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

Brown, Christine E.; Starr, Renate; Aguilar, Brenda; Shami, Andrew F.; Martínez, Camila; D’Apuzzo, Massimo; Barish, Michael E.; Forman, Stephen J.; Jensen, Michael C.

doi:10.1158/1078-0432.ccr-11-1669

Cited by 193 publications

(188 citation statements)

References 43 publications

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“…BBM1 (2 Â and injected orthotopically in the brain parenchyma of female NSG mice via stereotactic injection as described previously (19). Tumor growth was monitored at least once a week via optical imaging (Xenogen, LagoX) and flux signals were analyzed with Living Image software (Xenogen).…”

Section: In Vivo Tumor Studiesmentioning

confidence: 99%

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Priceman

Tilakawardane

Jeang

et al. 2018

Clinical Cancer Research

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225

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Purpose: Metastasis to the brain from breast cancer remains a significant clinical challenge, and may be targeted with CAR-based immunotherapy. CAR design optimization for solid tumors is crucial due to the absence of truly restricted antigen expression and potential safety concerns with “on-target off-tumor” activity. Here, we have optimized HER2-CAR T cells for the treatment of breast to brain metastases, and determined optimal second-generation CAR design and route of administration for xenograft mouse models of breast metastatic brain tumors, including multifocal and leptomeningeal disease. Experimental Design: HER2-CAR constructs containing either CD28 or 4-1BB intracellular costimulatory signaling domains were compared for functional activity in vitro by measuring cytokine production, T-cell proliferation, and tumor killing capacity. We also evaluated HER2-CAR T cells delivered by intravenous, local intratumoral, or regional intraventricular routes of administration using in vivo human xenograft models of breast cancer that have metastasized to the brain. Results: Here, we have shown that HER2-CARs containing the 4-1BB costimulatory domain confer improved tumor targeting with reduced T-cell exhaustion phenotype and enhanced proliferative capacity compared with HER2-CARs containing the CD28 costimulatory domain. Local intracranial delivery of HER2-CARs showed potent in vivo antitumor activity in orthotopic xenograft models. Importantly, we demonstrated robust antitumor efficacy following regional intraventricular delivery of HER2-CAR T cells for the treatment of multifocal brain metastases and leptomeningeal disease. Conclusions: Our study shows the importance of CAR design in defining an optimized CAR T cell, and highlights intraventricular delivery of HER2-CAR T cells for treating multifocal brain metastases. Clin Cancer Res; 24(1); 95–105. ©2017 AACR.

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Section: In Vivo Tumor Studiesmentioning

confidence: 99%

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Priceman

Tilakawardane

Jeang

et al. 2018

Clinical Cancer Research

Self Cite

225

161

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“…This targeting of IL-13Rα2 may be a novel approach to pharmacological intervention in brain tumors (34). A previous USA study (35) demonstrated that IL-13Rα2 was expressed by glioma stem-like cancer-initiating cells and differentiated tumor populations, rendering them targetable by IL-13Rα2-specific human CD8 + cytotoxic T cells (CTLs) [IL-13-zetakine + CTLs (36). Wang et al synthesized IL-13 cDNA de novo by PCR, the cDNA was ligated into the plasmid vector and the T cells were transfected.…”

Section: Targeting Il-13 and Its Receptors In Cancer Treatmentmentioning

confidence: 99%

“…In August, 2012, a novel mAb against IL-13Rα2, which competes with IL-13 for binding to IL-13Rα2 with high specificity and affinity, was generated and characterized (35). Therefore, studies assessing the therapeutic and diagnostic properties of this mAb in tumors are possible in the future.…”

Section: Targeting Il-13 and Its Receptors In Cancer Treatmentmentioning

confidence: 99%

Interleukin-13 and its receptors in colorectal cancer (Review)

Zhou

Shen

et al. 2013

Biomedical Reports

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Abstract. Interleukin (IL)-13 is an immunoregulatory cytokine secreted by numerous immune cells. Its functions are similar to those of IL-4 and they share a common receptor. This cytokine has been included in recent studies on human tumors and malignant diseases, evoking a scientific interest to investigate the role of IL-13 and its receptors as novel biomarkers and targets for therapy. Colorectal cancer is one of the most common human malignancies, its prognosis is not promising and the efficacy of molecular-targeted therapy has not been established. This review summarizes the currently available data on the role of IL-13 and its receptors in colorectal cancer, including the signaling pathways involved in mediating the effects of IL-13, the role of IL-13 and/or its receptors in the prediction of cancer and several drugs targeting IL-13 or its receptors that are currently under evaluation.

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“…IL-13RA2 is (i) associated with GBM patients' survival, (ii) expressed preferentially in a GBM mesenchymal subtype, and (iii) its gene, based on TCGA data, is overexpressed in 58% of patients (58; Figure 2B) and in the protein in up to 75% of GBM cases (35). IL-13RA2 was readily detected in cells isolated as GSC (59,60) and appears to contribute to GBM cell stemness. For example, GBM cells selected for lack of IL-13RA2 have a significantly lower stem cell-like forming and tumorigenic potential (61).…”

Section: Attractive Molecular Targets In Gbmmentioning

confidence: 99%

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

2017

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Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. One of the major obstacles to GBM treatment is the adequate properties of drugs. Complex pathobiology of GBM, including local invasion and intratumoral heterogeneity, represent major challenges to generating effective therapies. We discuss here the design of targeted cytotoxic drugs with an increased access to tumors and pathophysiologically important tumor compartments. Our research and others' have shown that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, and EphA3 receptors are overexpressed in most patients with GBM, but not in normal brain, and also in spontaneous canine high-grade gliomas like GBM, an excellent translational model of GBM. These receptors and also the EphB2 receptor are overexpressed and are functional in several GBM compartments involved Delivering Cytotoxic Therapies to Glioblastoma 342 in tumor progression and/or resistance to therapies. We pursue the novel idea of targeting all four receptors with one targeted cytotoxic compound (QUAD-CTX). We are constructing a molecularly targeted anti-GBM drug that (i) may not require patient prescreening, (ii) will attack most tumor compartments known to be pathobiologically important, and (iii) performs these functions in one pharmaceutical entity, so it will be suitable for monotherapy. We thus wish to take advantage of a unique opportunity to produce an off-the-shelf, highly specific, molecularly targeted drug candidate suitable to treat perhaps even all patients with GBM. We envision that this "molecular resection" will translate into clear-cut durable responses in patients suffering from this dreadful disease.

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

Cited by 193 publications

References 43 publications

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Regional Delivery of Chimeric Antigen Receptor–Engineered T Cells Effectively Targets HER2+ Breast Cancer Metastasis to the Brain

Interleukin-13 and its receptors in colorectal cancer (Review)

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

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