Glioblastoma Treatment: State-of-the-Art and Future Perspectives

Abstract

(1) Background: Glioblastoma is the most frequent and lethal primary tumor of the central nervous system. Through many years, research has brought various advances in glioblastoma treatment. At this time, glioblastoma management is based on maximal safe surgical resection, radiotherapy, and chemotherapy with temozolomide. Recently, bevacizumab has been added to the treatment arsenal for the recurrent scenario. Nevertheless, patients with glioblastoma still have a poor prognosis. Therefore, many efforts are being made in different clinical research areas to find a new alternative to improve overall survival, free-progression survival, and life quality in glioblastoma patients. (2) Methods: Our objective is to recap the actual state-of-the-art in glioblastoma treatment, resume the actual research and future perspectives on immunotherapy, as well as the new synthetic molecules and natural compounds that represent potential future therapies at preclinical stages. (3) Conclusions: Despite the great efforts in therapeutic research, glioblastoma management has suffered minimal changes, and the prognosis remains poor. Combined therapeutic strategies and delivery methods, including immunotherapy, synthetic molecules, natural compounds, and glioblastoma stem cell inhibition, may potentiate the standard of care therapy and represent the next step in glioblastoma management research.

Keywords: glioblastoma; immunotherapy; neurosurgery; radiotherapy; target therapy; temozolomide.

Figure 1

Vaccine Therapy. GB vaccines aim to generate an immune response by stimulating T cells and generating a cytotoxic response so that they attack the tumor through binding by specific receptors and MHC molecules. One of these receptors is EGFRvIII (Rindopepimut). Dendritic cell vaccines can be generated through stimulation by tumor cell lysate or peptides. Dendritic cells made with ex vivo glioma antigens migrate to lymphoid organs and activate T cells to subsequently attack the tumor. Customized vaccines are engineered through genetic engineering to the patient’s tumor-specific receptors. Abbreviations: DC: dendritic cell. MHC I: Major histocompatibility complex class I. TCR: T-cell receptor. IL-12: Interleukin-12. TNF-α: Tumor necrosis factor α CD8+ T cell: Cytotoxic T lymphocytes. Th cell: Helper T cell. CD40L: ligand CD40. Created with BioRender.com, accessed on 30 March 2022.

Figure 2

Oncolytic Virus Therapy Mechanism of Action. Oncolytic viruses (OVs) can be classified into two categories: natural viruses and genetically modified viruses. Modified viruses are loaded with specific receptors to recognize the GB through genetic engineering. The virus infects the tumor cells and generates either lysis, necrosis, or apoptosis, causing the release of tumor antigens, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). The antigen-presenting cells present these antigens to T-lymphocytes, promoting activation of an adaptive immune response. TCR: T-cell receptor; NK: natural killer MHC I: Major histocompatibility complex class II. MHC II: Major histocompatibility complex class II. DAMPs: Damage-associated molecular patterns; PAMPs: Pathogen associated molecular patterns. Created with BioRender.com.

Figure 3

Target receptors of oncolytic virus therapy. HSV-1: Herpes simplex virus 1; HVEM: herpes virus entry mediator SLAM: signaling lymphocyte activation molecule. Created with BioRender.com.

Figure 4

Checkpoint Inhibitors Mechanism of Action. Tumor cells evade the immune system as a defense mechanism. PD-L1 expression on tumor cells binds to PD-1 expressed on T cells, generating anergy of cytotoxic T cells. CTLA-4 expressed on T cells when it binds to B7 increases the expression of T-regs, generating an immunosuppressive response. CTLA-4 has a higher affinity for B7 than CD28 (B7 and CD28 when bound activate cytotoxic T cells). Monoclonal antibodies antagonize CTLA-4, PD-1, and PD-L1 preventing suppression of the immune response by cytotoxic T cells. Abbreviations: CTLA-4, cytotoxic T lymphocyte antigen 4; DC, dendritic cell; MHC, major histocompatibility complex; PD-L1, programmed cell death ligand-1; PD-1, programmed cell death-1; TCR, T-cell receptor; T-regs, regulatory T cells. Created with BioRender.com.

Figure 5

CAR T Cells Therapy. (1) T cells are extracted from the peripheral blood of patients, then (2) they are ex-vivo amplified and genetically remodeled so that (3) they express specific chimeric antigen receptor (CAR) in the cell membrane. (4) CAR T cells are injected back again in the patient, which can (5) specificallyrecognize the tumor cells and induce apoptosis. Created with BioRender.com.