Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy

Thaçi, Bart; Brown, Christine E.; Binello, Emanuela; Werbaneth, Katherine; Sampath, Prakash; Sengupta, Sadhak

doi:10.1093/neuonc/nou045

Cited by 143 publications

(112 citation statements)

References 76 publications

(101 reference statements)

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“…Two Phase 1 clinical trials were performed with intracranial administration of first-generation IL-13 zetakine T cell clones in patients with high-grade gliomas [152]. In the pilot trial, 3 participants with recurrent/refractory GBM were treated with autologous first generation IL-13 zetakine T-cell clones in escalating cell dose infusion cycles (NCT00730613) [153].…”

Section: Chimeric Antigen Receptor-modified T Cellsmentioning

confidence: 99%

“…All 6 patients were treated in conjunction with IL-2 with repetitive doses of CAR T cells. In both clinical trials, the feasibility of this approach was demonstrated [152]. Because all types of CAR-T cells expressing IL-13 or its mutants will bind to IL-13Ra1 in tumor and non-tumor cells, the investigators should be careful in monitoring on-target and off-target toxicity closely.…”

Section: Chimeric Antigen Receptor-modified T Cellsmentioning

confidence: 99%

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

et al. 2015

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Section: Chimeric Antigen Receptor-modified T Cellsmentioning

confidence: 99%

Section: Chimeric Antigen Receptor-modified T Cellsmentioning

confidence: 99%

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

et al. 2015

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“…The first-generation CAR-modified T cells targeted to IL13Rα2 produced impressive results in preclinical studies, curing mice with intracranial glioma without any recurrence. In phase I trials, they were found to be safe and capable of trafficking to distant sites of infiltrative disease [35]. Second-generation IL13Rα2-CAR T cell clones linked to CD28 costimulatory molecule and CD3 are awaiting trials and may offer superior efficacy.…”

Section: Immunotherapiesmentioning

confidence: 99%

Targeted Therapeutics in Patients With High-Grade Gliomas: Past, Present, and Future

Chen

Cohen

Colman

2016

Curr. Treat. Options in Oncol.

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High-grade gliomas remain incurable despite current therapies, which are plagued by high morbidity and mortality. Molecular categorization of glioma subtypes using mutations in isocitrate dehydrogenase 1/2 (IDH1/2), TP53, and ATRX; codeletion of chromosomes 1p and 19q; DNA methylation; and amplification of genes such as epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor, alpha polypeptide provides a more accurate prognostication and biologic classification than classical histopathological diagnoses, and a number of molecular markers are being incorporated in the new World Health Organization classification of gliomas. However, despite the improved understanding of the molecular subtypes of gliomas and the underlying alterations in specific signaling pathways, these observations have so far failed to result in the successful application of targeted therapies, as has occurred in other solid tumors. To date, the only targeted therapy for gliomas approved by the US Food and Drug Administration is bevacizumab, which targets vascular endothelial growth factor. EGFR remains a dominant molecular alteration in specific glioma subtypes and represents a potentially promising target, with drugs of multiple types targeting EGFR in development including vaccines, antibody drug conjugates, and chimeric antigen receptor (CAR) T cells, despite the prior failures of EGFR tyrosine kinase inhibitors. Immune therapies under investigation include checkpoint inhibitors, vaccines against tumor-associated antigens and tumor-specific antigens, pulsed dendritic cells, heat shock protein-tumor conjugates, and CAR T cells. Mutations in the IDH1/2 genes are central to gliomagenesis in a high proportion of grade II and III gliomas, and ongoing trials are examining vaccines against IDH1, small molecular inhibitors of IDH1 and IDH2, and metabolic components including NAD+ depletion to target IDH-mutated gliomas. The central role of DNA methylation in a subset of gliomas may be targetable, but better understanding of the relation between epigenetic alterations and resulting tumor biology appears necessary. Ultimately, given the prior failure of single-agent targeted therapy in high-grade gliomas, it appears that novel combinatorial therapy or targeted drugs with immunomodulatory or epigenetic approaches will likely be necessary to successfully combat these challenging tumors.

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“…A number of TAAs have been identified in glioblastoma, including EphA2, Her2, IL13Ra2, gp100, Mage-1, survivin, hTERT, AIM2, and EGFR (Koka et al, 2003;Tchirkov et al, 2003;Liu et al, 2004a, b;Heimberger et al, 2005;Wykosky and Debinski, 2008;Shirai et al, 2009;Thaci et al, 2014). The discovery of glioblastomaspecific antigens has led to the development of vaccines targeted against them.…”

Section: Vaccination Therapymentioning

confidence: 99%