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Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma.

ABSTRACT: Glioblastoma multiforme (GBM) presents the most malignant form of glioma, with a 5-year survival rate below 3% despite standard therapy. Novel immune-based therapies in improving treatment outcomes in GBM are therefore warranted. Several molecularly defined targets have been identified mediating anti-GBM cellular immune responses. Mesothelin is a tumor-associated antigen (TAA) which is expressed in several solid tumors with different histology. Here, we report the immunological significance of mesothelin in human malignant glioma. Expression of mature, surface-bound mesothelin protein was found to bein human GBM defined by immunofluorescence microscopy, and on freshly isolated, single cell suspension of GBM tumor cells and GBM tumor cell lines, determined by based on flow cytometric analysis. Peripheral blood (PB) from patients with GBM, stimulated with mesothelin peptides and IL-2, IL-15 and IL-21, exhibited increased antigen-specific IFN-? and TNF-? production. Anti-mesothelin directed T-cell responses could also be detected in tumor - infiltrating lymphocytes (TIL) isolated from GBM speciments. Furthermore, T cells cultured in the presence of IL-2, IL-15 and IL-21 displayed enhanced mesothelin-specific CD4+ and CD8+ subset proliferation, based on ELISA and flow cytometric readouts. Mesothelin-specific IgG antibodies as well as (shed) mature mesothelin protein were detected in plasma samples from patients with GBM by indirect ELISA. Finally yet importantly, we identified distinct immune recognition hotspots within the mature mesothelin component, defined by peptide-specific IFN-? responses from peripheral T-cells from patients with GBM. Mesothelin may therefore qualify as a viable target for immunotherapeutic approaches for patients with GBM.

SUBMITTER: Liu Z

PROVIDER: S-EPMC5655191 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma.

Liu Zhenjiang Z Rao Martin M Poiret Thomas T Nava Silvia S Meng Qingda Q von Landenberg Anna A Bartek Jiri J Xie Shanshan S Sinclair Georges G Peredo Inti I Dodoo Ernest E Maeurer Markus M

Oncotarget 20170816 46

Glioblastoma multiforme (GBM) presents the most malignant form of glioma, with a 5-year survival rate below 3% despite standard therapy. Novel immune-based therapies in improving treatment outcomes in GBM are therefore warranted. Several molecularly defined targets have been identified mediating anti-GBM cellular immune responses. Mesothelin is a tumor-associated antigen (TAA) which is expressed in several solid tumors with different histology. Here, we report the immunological significance of m ...[more]

PMID: 29113296

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Project description:Abstract BACKGROUND Glioblastoma is the most common malignant primary brain tumor in adults with an urgent need for novel treatment options. The administration of pro-inflammatory cytokines could be a potent immunotherapeutic approach to shift the balance between tumor-associated immunosuppression and immune activation. However, the systemic administration of therapeutically active doses of pro-inflammatory cytokines is not feasible due to toxic side effects and there is a need for strategies that enable a targeted delivery of pro-inflammatory cytokines to the tumor site. METHODS We investigated different antibody-cytokine fusion products that enable a targeted delivery of interleukin (IL)-2, IL-12 or tumor necrosis factor (TNF)-α to the tumor site by binding to a tumor-specific epitope of fibronectin. We investigated the expression of this tumor-specific epitope ex vivo in tumor-bearing mouse brains and human glioblastoma samples. Subsequently, we assessed the anti-tumor activity of IL-2, IL-12 or TNF-α fused to an antibody targeting this tumor-specific epitope in orthotopic syngeneic mouse glioma models. RESULTS The tumor-specfic extra domain B of fibronectin is expressed in murine glioma models and human glioblastoma samples. A fluorochrome-labeled antibody targeting this tumor-specific epitope accumulated at the tumor site in the brain in vivo upon systemic administration. IL-2, IL-12, or TNF-α fused to this antibody conferred a survival benefit in orthotopic tumor-bearing mice and cured a fraction of tumor-bearing mice. Mechanistically, antibody-fused TNF-α induced tumor necrosis and increased the activation of tumor-infiltrating natural killer (NK) cells, whereas antibody-fused IL-12 mainly boosted an anti-tumor immune response mediated by NK cells and T cells. CONCLUSION We demonstrate the expression of a tumor-specific epitope of fibronectin in glioblastoma and exploit this for the targeted delivery of IL-2, IL-12 or TNF-α to the tumor site. Our preclinical assessments indicate potent anti-tumor activity in orthotopic, syngneic glioma mouse models and reveal the mode of action for the different immunocytokines. Based on these findings, we initiated a phase I/II clinical trial in patients with recurrent glioma to investigate the targeted delivery of TNF-α (ClinicalTrials.gov identifier NCT03779230).

Dataset Information

Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma.

Publications

Mesothelin as a novel biomarker and immunotherapeutic target in human glioblastoma.

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