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Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy.

ABSTRACT: Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited.The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha2 (IL-13Ralpha2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived tumor's response to a selective cytotoxin.Expression of IL-13Ralpha2 was evaluated in a panel of 25 human pheochromocytoma clinical samples by RT-PCR and eight MPC tumors by indirect immunofluorescence assay and RT-PCR.The function of IL-13Ralpha2 in these tumor cells was examined by evaluating tumor sensitivity to a recombinant IL-13-Pseudomonas exotoxin (IL-13PE). Subcutaneous small and large MPC tumors in athymic nude mice (n = 10) were treated intratumorally with IL-13PE (100 m icrog/kg).IC(50) and tumor size were measured.IL-13PE immunotoxin was highly cytotoxic to IL-13Ralpha2-overexpressing MPC cells (IC(50) <2.5 ng/ml) in vitro. Furthermore, IL-13PE was highly cytotoxic to sc tumors. Our results showed a statistically significant decrease in tumor size as early as 3 d after initial treatment and further suppressed growth of MPC tumors. All tumors displayed a histological evidence of necrosis in response to IL-13 immunotoxin without any adverse effects in host at this dose.Human and murine neuroendocrine pheochromocytoma overexpress the IL-13Ralpha2 chain, and an IL-13PE-based receptor-directed anticancer approach may prove useful in treatment for metastatic pheochromocytoma patients.

SUBMITTER: Lai EW

PROVIDER: S-EPMC2730867 | biostudies-other | 2009 Aug

REPOSITORIES: biostudies-other

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Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy.

Lai Edwin W EW Joshi Bharat H BH Martiniova Lucia L Dogra Ritika R Fujisawa Toshio T Leland Pamela P de Krijger Ronald R RR Lubensky Irina A IA Elkahloun Abdel G AG Morris John C JC Puri Raj K RK Pacak Karel K

The Journal of clinical endocrinology and metabolism 20090602 8

<h4>Context</h4>Pheochromocytomas and paragangliomas are rare catecholamine-secreting neuroendocrine tumors arising from the adrenal medulla and sympathetic tissues. When complete surgical resection is not an option, the treatment of pheochromocytoma is limited.<h4>Objective</h4>The objective of the study was to identify and characterize overexpression of IL-13 receptor-alpha2 (IL-13Ralpha2) gene expression in human and murine tumors and verify xenograft mouse pheochromocytoma cell (MPC)-derived ...[more]

PMID: 19491224

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Project description:Background Interleukin-13 receptor α 2 (IL13Rα2) is a promising tumor-directed antigen of malignant glioma (MG). Here, we examine the efficacy and safety of T cells containing a YYB-103 chimeric antigen receptor (CAR) that can preferentially bind to IL13Rα2 on MG cells. Methods IL13 was modified on the extracellular domain by substitution of amino acids with E13K, R66D, S69D, and R109K and stably transfected into human T cells using a retroviral vector. The in vitro efficacy of YYB-103 CAR T cells was tested in cell lines with differing IL13Rα1 and IL13Rα2 expression. The in vivo efficacy of intracerebroventricular (i.c.v.) and intravenous (i.v.) routes of YYB-103 CAR T-cell administration were tested in orthotopic MG mouse models. Immunohistochemical staining of MG was performed using WHO grade 3/4 surgical specimens from 53 patients. IL13Rα2 expression was quantified by H-score calculated from staining intensity and percentage of positive cells. Results Binding affinity assay of YYB-103 verified apparently nil binding to IL13Rα1, which was more selective than previously reported IL13 modification (E13Y). YYB-103 CAR T cells showed selective toxicity toward co-cultured U87MG (IL13Rα1+/IL13Rα2+) cells but not A431 (IL13Rα1+/IL13Rα2−) cells. Consistently, YYB-103 CAR T cells suppressed tumor growth in nude mice receiving orthotopic injection of U87 MG cells. Both i.c.v. and i.v. injections of YYB-103 CAR T cells reduced tumor volume and prolonged overall survival of tumor-bearing mice. The median H-score for IL13Rα2 in patient-derived MG tissue was 5 (mean, 57.5; SD, 87.2; range, 0 to 300). Conclusion This preclinical study demonstrates the efficacy of IL13Rα2-targeted YYB-103 CAR T cells against MG cells. The use of modified IL13 to construct a CAR facilitated the selective targeting of IL13Rα2-expressing MG cells while sparing IL13Rα1-expressing cells. Notably, YYB-103 CAR T cells exhibited effective blood–brain barrier crossing, suggesting compatibility with i.v. administration rather than intracranial injection. Additionally, the high H-score for IL13Rα2 in glioblastoma, especially in conjunction with the poor prognostic markers of wild-type isocitrate dehydrogenase-1 (IDH-1) and unmethylated O6-methyl guanine methyl-transferase (MGMT), could be used to determine the eligibility of patients with recurrent glioblastoma for a future clinical trial of YYB-103 CAR T cells.

Project description:BACKGROUND:The development of therapeutic vaccines requires thorough knowledge of potential hazards associated with long-term inactivation of self-proteins. Among potential targets, interleukin 13 (IL-13) merits consideration, as monoclonal antibodies disrupting IL-13 signaling are proving to be exceedingly effective in common conditions such as atopic dermatitis. OBJECTIVE:Given the mass publication of scientific data, an appraisal of safety aspects is challenging. METHODS:We here provide a three-fold approach to survey clinically relevant information on off-target effects, both adverse and beneficial, that may potentially be encountered in patients undergoing long-term IL-13 inactivation. First, we review non-clinical data in vivo and in vitro. Second, we summarize safety data accumulating from patients dosed with anti-IL-13 drugs. Third, we exploit human mutation data as well as emerging large-scale genetic datasets (global exome data from 60,000 patients) to obtain information on any association of IL-13-inactivating genetic variants with disease states. In addition, we: (1) dissect the precise efficacy signals obtained with various drugs targeting IL-13 and/or IL-4, and (2) summarize unintended, but potentially beneficial effects of prolonged IL-13 inactivation on several functional systems. RESULTS:Prolonged repression of IL-13 in several thousand patients so far has not uncovered any non-redundant functions of IL-13 in immune defense. Furthermore, missense mutations in the key genes IL-13, IL-13R?1, IL-13R?2, IL-4, IL-4R? are common, while no case reports have been published on any immune deficiency or increased risk of neoplastic disease associated with such mutations, suggesting that these genes do not harbor non-redundant roles in adult outbred humans. In terms of efficacy, data from clinically used drugs strongly suggest that targeting IL-13 only, as opposed to IL-13 and IL-4, may be effective in eczema while being more selective. Importantly, several lines of evidence suggest that inhibition of IL-13 may in fact harbor potentially beneficial effects on non-targeted systems, including glucose metabolism, hepatic fibrosis, and atherosclerosis, suggesting that respective outcomes should be systematically captured in patients dosed with IL-13 interfering drugs. Collectively, available evidence suggests that IL-13 may fulfill safety requirements required for the target of a therapeutic vaccine.

Dataset Information

Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy.

Publications

Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy.

Similar Datasets

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