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Review
. 2022 Apr 15;41(1):142.
doi: 10.1186/s13046-022-02349-7.

Emerging therapies for glioblastoma: current state and future directions

Liang Rong  1 , Ni Li  1 , Zhenzhen Zhang  2
Affiliations
Review

Emerging therapies for glioblastoma: current state and future directions

Liang Rong et al. J Exp Clin Cancer Res. .

Abstract

Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor with an extremely poor prognosis. Given the poor survival with currently approved treatments for GBM, new therapeutic strategies are urgently needed. Advances in decades of investment in basic science of glioblastoma are rapidly translated into innovative clinical trials, utilizing improved genetic and epigenetic profiling of glioblastoma as well as the brain microenvironment and immune system interactions. Following these encouraging findings, immunotherapy including immune checkpoint blockade, chimeric antigen receptor T (CAR T) cell therapy, oncolytic virotherapy, and vaccine therapy have offered new hope for improving GBM outcomes; ongoing studies are using combinatorial therapies with the aim of minimizing adverse side-effects and augmenting antitumor immune responses. In addition, techniques to overcome the blood-brain barrier (BBB) for targeted delivery are being tested in clinical trials in patients with recurrent GBM. Here, we set forth the rationales for these promising therapies in treating GBM, review the potential novel agents, the current status of preclinical and clinical trials, and discuss the challenges and future perspectives in glioblastoma immuno-oncology.

Keywords: CAR T, Oncolytic virotherapy; Focused ultrasound; Glioblastoma; Immune checkpoint blockade; Immunotherapy; Vaccine.

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Conflict of interest statement

The author declare that there is no conflict of interests regarding the publication of this paper.

Figures

Fig. 1
Fig. 1
Genetic and epigenetic alterations in the genesis of gliomas. Shown are the relationships between the molecular lesions and pathobiology in the different types of gliomas. IDH, socitrate dehydrogenase; RELA, transcription factor p65; CDKN, cyclin-dependent kinase inhibitor; YAP1, YES-associated protein 1; PF, posterior fossa; NF2, neurofibromin 2; SEGA, subependymal giant cell astrocytoma; TSC, tuberous sclerosis; RTK, receptor tyrosine kinase; PDGFRA, platelet-derived growth factor receptor-α; TERT, telomerase reverse transcriptase; PTEN, phosphatase and tensin homologue; EGFR, epidermal growth factor receptor; H3F3A, histone H3.3; HIST1H3B, histone H3.1; ACVR1, activin A receptor 1; ATRX, α-thalassemia/mental retardation syndrome X-linked; TP53, tumour protein p53; PPM1D, protein phosphatase 1D; MGMT, O-6-methylguanine-DNA methyltransferase; g-CIMP, glioma CpG island methylator phenotype; Chr., chromosome; CIC, Drosophila homologue of capicua; Those IDH-mutant glioblastomas derived by progression from pre-existing lower grade astrocytomas (blue arrow) are tend to manifest in younger patients (≤50 years of age) compared with IDH wild-type tumors
Fig. 2
Fig. 2
General structure of CAR and CAR T-cell therapy. a Basic structure of T-cell receptor (TCR). The TCR comprise variable TCR-α and -β chains coupled to three dimeric signaling transduction modules CD3 δ/ε, CD3 γ/ε and CD3 ζ/ζ. T cell activation usually requires MHC matching. b Structure of 1st- 4th generation CARs. Chimeric antigen receptor (CAR) are fusion proteins consisting of an extracellular domain with a tumor-binding moiety, typically a single-chain variable fragment (scFv), followed by a hinge of varying length and flexibility, a transmembrane (TM) region, and one or more intracellular signaling domains associated with the T-cell signaling. First-generation CARs contain the stimulatory domain of CD3ζ, whereas second-generation CARs possess a co-stimulatory domain (typically CD28 or 4-1BB) fused to CD3ζ to ensure full activation. Third-generation CARs consist of two co-stimulatory domains linked to CD3ζ to maximize signaling activation. The first co-stimulatory domain is either a CD28 or a 4-1BB domain, with the second co-stimulatory domain consisting of either a CD28, a 4-1BB or a OX40 domain. The fourth-generation CARs, combine the second-generation CAR with the addition of various genes, including cytokines and co-stimulatory ligands, to enhance the tumoricidal effect of the CAR T cells. c Mechanisms of CAR-T therapy. CAR-T cells can produce an artificial T cell receptor that has high affinity to a tumor-specific surface antigen. BiTEs can redirect T cells to tumor cell surface antigens and activate T cells. Activated T cells release perforin and other granzymes through immunological synapses. These cytolytic proteins can form pores on tumor cell surface, and thus are endocytosed by tumor cells and then form endosomes and lyse tumor cells ultimately form endosomes in tumor cells and lyse tumor cells ultimately
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