Abstract
Glioblastoma (GBM) is the most frequent and aggressive primary central nervous system tumor. Surgery followed by radiotherapy and chemotherapy with alkylating agents constitutes standard first-line treatment of GBM. Complete resection of the GBM tumors is generally not possible given its high invasive features. Although this combination therapy can prolong survival, the prognosis is still poor due to several factors including chemoresistance. In recent years, a comprehensive characterization of the GBM-associated molecular signature has been performed. This has allowed the possibility to introduce a more personalized therapeutic approach for GBM, in which novel targeted therapies, including those employing tyrosine kinase inhibitors (TKIs), could be employed. The GBM tumor microenvironment (TME) exerts a key role in GBM tumor progression, in particular by providing an immunosuppressive state with low numbers of tumor-infiltrating lymphocytes (TILs) and other immune effector cell types that contributes to tumor proliferation and growth. The use of immune checkpoint inhibitors (ICIs) has been successfully introduced in numerous advanced cancers as well as promising results have been shown for the use of these antibodies in untreated brain metastases from melanoma and from non-small cell lung carcinoma (NSCLC). Consequently, the use of PD-1/PD-L1 inhibitors has also been proposed in several clinical trials for the treatment of GBM. In the present review, we will outline the main GBM molecular and TME aspects providing also the grounds for novel targeted therapies and immunotherapies using ICIs for GBM.
Highlights
Regarding the role of other Long non-coding RNAs (LncRNAs), evidence has been reported about the fact that the high expression of other LncRNAs such as maternally expressed gene 3 (MEG3), metastasis associated lung adenocarcinoma (MALAT1), cancer susceptibility candidate 2 (CASC2), taurineupregulated gene 1 (TUG1), DBH antisense RNA 1 (DBH-AS1), AC005035.1, AC010336.2, AC108134.2, AC116351.2, Clorf132, C10orf91, LINC00475, MIR210HG could be associated with poor outcome in GBM cases (Zeng et al, 2018)
An investigational immunotherapy study of nivolumab compared to temozolomide, each given with radiation therapy, for newly diagnosed patients with glioblastoma (GBM, a malignant brain cancer) Translational study of nivolumab in combination with bevacizumab for recurrent glioblastoma Immunological and functional characterization of cellular population CD45+ infiltrating human glioblastoma
Glioblastoma tumors of cases non-responsive to immune checkpoint inhibitors (ICIs) have shown an enrichment in mutations of the phosphatase and tensin homolog (PTEN) gene (Zhao et al, 2019) that has been associated with an immunosuppressive tumor microenvironment (TME) characterized by the presence of GBM cells expressing CD44
Summary
Glioblastoma (GBM) is the most common and aggressive primary CNS tumor (Stupp et al, 2009; Louis et al, 2016; Mendes et al, 2018; Altmann et al, 2019; Ostrom et al, 2019) and it has been included in the group of diffuse astrocytic and oligodendroglial tumors by the 2016 CNS WHO (Louis et al, 2016). Standard of care first-line treatment is constituted by maximal surgical resection (complete resection is performed quite rarely because of the presence of diffuse infiltrations), followed by radiotherapy with concomitant and adjuvant chemotherapy such as the oral alkylating agent, temozolomide (TMZ) Upon this treatment combination GBM show a median OS of about 15 months (Canoll and Goldman, 2008; Stupp et al, 2009; Ohgaki and Kleihues, 2013; Levine et al, 2015). We will outline the principal GBM molecular and tumor microenvironment (TME) aspects providing the grounds for novel targeted therapies and immunotherapy approaches using ICIs for the treatment of GBM affected patients
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