Updates in Glioblastoma Immunotherapy: An Overview of the Current Clinical and Translational Scenario

Abstract

Glioblastoma (GBM) is the most common and aggressive central nervous system tumor, requiring multimodal management. Due to its malignant behavior and infiltrative growth pattern, GBM is one of the most difficult tumors to treat and gross total resection is still considered to be the first crucial step. The deep understanding of GBM microenvironment and the possibility of manipulating the patient’s innate and adaptive immune system to fight the neoplasm represent the base of immunotherapeutic strategies that currently express the future for the fight against GBM. Despite the immunotherapeutic approach having been successfully adopted in several solid and haematologic neoplasms, immune resistance and the immunosuppressive environment make the use of these strategies challenging in GBM treatment. We describe the most recent updates regarding new therapeutic strategies that target the immune system, immune checkpoint inhibitors, chimeric antigen receptor T cell therapy, peptide and oncolytic vaccines, and the relevant mechanism of immune resistance. However, no significant results have yet been obtained in studies targeting single molecules/pathways. The future direction of GBM therapy will include a combined approach that, in contrast to the inescapable current treatment modality of maximal resection followed by chemo- and radiotherapy, may combine a multifaceted immunotherapy treatment with the dual goals of directly killing tumor cells and activating the innate and adaptive immune response.

Coactosin-Like Protein 1 (COTL1) Could Be an Immunological and Prognostic Biomarker: From Pan-Cancer Analysis to Low-Grade Glioma Validation

“…Immune checkpoint inhibition, particularly the targeted modulation of the PD-1/PD-L1 and CTLA-4 inhibitory pathways, has emerged as a central focus in the investigation of GBM-induced immunosuppression. 24 The positive association between COTL1 expression and a favorable response to ICIs suggests that COTL1 may play a role in bolstering the immune response against tumors. Our investigation has unveiled a notable correlation between COTL1 and various immune parameters, including immune cell infiltration, immunoregulatory genes, and immune checkpoint genes.…”

Non-cellular immunotherapies in pediatric central nervous system tumors

“…TAMs are thought to “polarize” depending on signaling, stimulus, and pathology into either pro-inflammatory (immunoactive) or anti-inflammatory (immunosuppressive) states ( 27 – 30 ). Brain tumor-associated TAMs are pro-tumorigenic in a number of ways, such as upregulation of endothelial cell secretion of vascular endothelial growth factor (VEGF), secretion of immunosuppressive cytokines such as transforming growth factor beta (TGF-β) and interleukin 10 (IL-10), secretion of arginase (to starve T-cells), secretion of epidermal growth factor (EGF) to promote tumor migration, secretion of pro-tumor chemokines and cytokines, secretion of prostaglandins (to inhibit activation of T-cells), and direct antigen presentation functions ( 30 – 33 ). Additional non-TAM myeloid-derived suppressor cells (MDSCs), are a group of cells of myeloid origin that are pathologically activated and serve an immunosuppressive function against both adaptive and innate anti-tumor immunity ( 34 – 36 ).…”

Liquid Biopsy for Glioma Using Cell-Free DNA in Cerebrospinal Fluid

“…Effective liquid biopsy methods may solve these problems in the clinical management of glioma. Furthermore, advances in our understanding of the tumor microenvironment of glioma and advances in immunotherapy have underscored the importance of assessing bodily fluid biomarkers for therapeutic planning and clinical management [ 30 , 31 , 32 , 33 ].…”