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Table of Contents
REVIEW
Year : 2018  |  Volume : 1  |  Issue : 3  |  Page : 79-88

The advances in targeted therapy and immunotherapy for glioblastoma: Basic research and clinical trials


1 Department of Pathology, School of Basic Medical Sciences and The Affiliated Sir Run Run Hospital, Nanjing Medical University; Department of Microbiology and Immunology, Southeast University, Nanjing, Jiangsu, China
2 Department of Neurosurgery, The Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Hubei, China
3 Department of Oncology, The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
4 Department of Pathology, School of Basic Medical Sciences and The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing, Jiangsu, China
5 Department of Integrated Medicine, Guangdong Well Clinic and Union Doctor Group, Guangzhou, Guangdong, China
6 Department of Neurosurgery, First Hospital of Jilin University, Changchun, Jilin, China
7 Department of Pathology, School of Basic Medical Sciences and The Affiliated Sir Run Run Hospital, Nanjing Medical University; Department of Microbiology and Immunology, Southeast University, Nanjing, Jiangsu; Department of Neurosurgery, The Affiliated Yijishan Hospital of Wannan Medical College, Wuhu, Hubei, China

Date of Web Publication29-Jun-2018

Correspondence Address:
Dr. Hongping Xia
Department of Pathology, School of Basic Medical Sciences and The Affiliated Sir Run Run Hospital, Nanjing Medical University, Nanjing 21116, Jiangsu
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/glioma.glioma_10_18

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  Abstract 

Glioblastoma (GBM) is the most common and fatal type of malignant central nervous system tumor with high invasion. The median overall survival of GBM is only around 14 months by standard treatment, which conventionally consists of surgical resection, followed by radiotherapy and adjuvant chemotherapy with temozolomide (TMZ). Currently, TMZ, carmustine, lomustine, and bevacizumab are the therapeutic drugs for GBM approved by the US Food and Drug Administration. Due to the progress of molecular genetics in tumor therapy, new targeted therapy drugs are continuously emerging for GBM. Meanwhile, immunotherapies, such as immune checkpoint inhibitors, tumor vaccines, and chimeric antigen receptor T (CAR-T) cell therapy, have also made great achievements in clinical trials. The combination of molecular targeted therapy and immunotherapy of GBM has become the focus of current research. It shows promise in GBM treatment and gives new hope to patients. This review focuses on recent advances in targeted therapy and immunotherapy and discusses their combined treatment of GBM.

Keywords: Chimeric antigen receptor T-cell therapy, glioblastoma, immune checkpoint inhibitors, immunotherapy, targeted therapy


How to cite this article:
Wang M, Jiang X, Wu F, Xu H, Lin Z, Qi B, Xia H. The advances in targeted therapy and immunotherapy for glioblastoma: Basic research and clinical trials. Glioma 2018;1:79-88

How to cite this URL:
Wang M, Jiang X, Wu F, Xu H, Lin Z, Qi B, Xia H. The advances in targeted therapy and immunotherapy for glioblastoma: Basic research and clinical trials. Glioma [serial online] 2018 [cited 2022 Dec 7];1:79-88. Available from: http://www.jglioma.com/text.asp?2018/1/3/79/235647


  Introduction Top


Glioblastoma (GBM) is one of the most common and lethal type of gliomas, accounting for nearly half of primary malignant brain tumors. For malignant tumors, the incidence rate and the number of cases are highest for GBM. Relative survival estimated for GBM is very low, and the 5-year survival rate is only approximately 5.5%.[1] GBM is a Grade IV cancer according to the WHO classifications of Central Nervous System (CNS) tumors [2] and shows infiltrative growth, duration of rapid progress, and often relapses soon after surgical resection. Although the treatment of GBM has developed into a combined treatment mode of surgery, radiotherapy, and chemotherapy, its prognosis is still very poor.[3] In particular, the median survival of newly diagnosed GBM patients is only approximately 1 year and nearly insensitive to therapy. In recent years, the core signaling pathway-directed therapy (e.g., targeted receptor tyrosine kinase [RTK]/RAS/phosphatidylinositol 3-kinase [PI3K], p53, and retinoblastoma [RB] pathway, and cell molecular level in GBM [4]) has become a hot research topic and can aid in personalized therapy, indicating clinical design for GBM patients. Tumor vaccines, monoclonal antibodies, oncolytic viruses (OVs), and adoptive immunotherapies also have achieved encouraging results both in the laboratory and in the clinic [Figure 1]. Comprehensive treatment, including molecular targeted therapy and immunotherapy or combined treatment, will play key parts in the treatment of GBM in the future.
Figure 1: The core pathway-directed therapy targeted Ras/phosphatidylinositol 3-kinase, p53, retinoblastoma, and different cell molecular connections in glioblastoma. Tumor vaccines, monoclonal antibodies, oncolytic viruses, and adoptive immunotherapy also have achieved encouraging results both in the laboratory and in the clinic, showing a promising application prospect

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  Target Therapy of Glioblastoma Top


Molecular targeted therapy has made great progress in the last 10 years. Bevacizumab (BEV), a monoclonal antibody (mAb) targeted vascular endothelial growth factor (VEGF), was the third drug approved by the Food and Drug Administration (FDA) for the treatment of recurrent GBM in 2009.[5] However, regardless of relapsed versus newly diagnosed GBM patients, BEV does not significantly increase overall survival (OS) although it improves radiation sensitivity and prolongs progression-free survival (PFS).[6] Therefore, with an in-depth understanding of the molecular pathology of GBM, the new signal transduction pathways that drive tumorigenesis and the development of glioma may become new therapeutic targets for precision medicine. Novel molecular targeted drugs that can be more effective in related pathways remain an urgent need. Here, we presented the theoretical basis for molecular targeted pathways, ligand receptors, cytokines, viruses, and other target markers. We also discussed the difficulties and prospects of immunotherapy and molecular targeted therapies in GBM.

Intracellular signaling pathway

In recent years, three core signaling pathways have been identified by The Cancer Genome  Atlas More Details (TCGA) network study in the pathogenesis of malignant glioma: RTK pathway, tumor protein p53 pathway, and retinoblastoma (RB) protein tumor suppressor signal transduction pathway. These have exhibited 88%, 87%, and 78% aberrations, respectively.[4] In addition, other typical signaling pathways, such as angiogenesis pathways, are also important to the development of GBM. However, the p53 and RB pathways are difficult to be used as therapeutic targets. The current therapeutic research mainly focuses on targeting gene amplification, mutation, and overexpression of RTK/RAS/PI3K signaling pathways.[7]

Activated Ras protein in GBM can promote the growth of tumor cells by activating the mitogen-activated protein kinase (MAPK) pathway and PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. Dysregulations of MAPK and PI3K signaling are found in GBM pathogenesis, and their positive expression rates are closely related to the clinical grade of GBM, as well as the poor prognosis of patients.[8] NF1 as a RAS suppressor gene has at least 23% aberrant expression (inactivated, mutated, or deleted) in GBM patients, suggesting the importance of NF1 in human GBM.[4] Up to 50% of high-grade GBM tumors are phosphatase and tensin homolog (PTEN) gene deficient. PTEN is a major tumor suppressor molecule inhibiting PI3K downstream of epidermal growth factor receptor (EGFR), and inactivation of mutations leads to uncontrolled PI3K signaling, activation of AKT, and abnormal proliferation of tumor cells. Activation of mTOR downstream of AKT activates protein translation, enhances cell growth, inhibits apoptosis, and accelerates cell invasion.[9]

Studying the biological method of inhibiting the activation of the Ras protein is a key to the targeted therapy of GBM. Farnesyltransferase is a key enzyme in the process of Ras activation, and farnesyltransferase inhibitors are currently the main targeted drugs for clinical evaluation. In particular, tipifarnib and lonafarnib have been used in phase I clinical trials.[10] In many cases, BRAF inhibitor (dabrafenib) combined with MEK inhibitor (trametinib) therapy has been shown to cause dramatic clinical and radiographic responses in high-grade glioma (HGG) patients with BRAF mutation.[11] At present, blocking the PI3K/mTOR cascade signal is equally important. Everolimus (mTOR inhibitor) has been evaluated by the phase I–II trial (NCT00411619). Long-term everolimus treatment may reduce tumor size safely and effectively.[12] In addition to dual PI3K/mTOR inhibitors, GSK2126458, PKI-587, and buparlisib (NVP-BKM120),[13] a novel second-generation dual inhibitor that targets both PI3K and mTOR, voxtalisib (XL765) in combination with temozolomide (TMZ), shows safety and moderate PI3K/mTOR inhibiting activity.[14] Recently, hyperpolarized 13C magnetic resonance spectroscopic imaging can potentially assess the therapeutic effect of PI3K/mTOR inhibitors in GBM models.[15] Besides changes of p53 itself, alterations of the p53-interacting network also include CDKN2A homozygous mutations and deletions (49%), amplification of MDM2 (14%), and amplification of MDM4 (7%). These genes are all potential drug targets to be developed for the p53 pathway.[4] The main targeted drugs for the RB pathway are CDK2 inhibitors (dinaciclib and purvalanol) and CDK4/6 inhibitor (LY2835219) in glioma.[16]

Epidermal growth factor receptor pathway

EGFR is a tyrosine kinase receptor on the surface of cells, which is highly and frequently expressed in primary GBM. Almost 45% alterations have been observed (41 of the 91 GBM cases) according to the TCGA.[17] EGFRvIII, the most common variant of EGFR, is only found in GBM and other tumor cell surface without expression in normal tissue cells and therefore has very high tumor specificities.[18] EGFRvIII can be used as a specific biomarker of some tumors for biological targeted therapy.

Biological targeted therapy targets the pathway of the EGF/EGFR ligand and involves the use of mAb against EGFR, such as cetuximab and nimotuzumab, and tyrosine kinase inhibitors (TKIs), including gefitinib, erlotinib, afatinib, canertinib, and lapatinib. A current retrospective study carried out based on clinical trials found that both gefitinib and erlotinib had good therapeutic responses in GBM patients with co-expression of EGFRvIII and PTEN.[19] Cetuximab has been used in phase I and phase II clinical trials, demonstrating effective improvement in the treatment for patients with GBM.[20] A clinical trial has been initiated to determine the therapeutic effect of ABT-414, an anti-EGFR antibody–drug conjugate. Radiotherapy followed adjuvant therapy with combination of ABT-414 and TMZ and has shown promising results in OS among participants with newly diagnosed GBM with EGFR amplification (NCT02573324).[21] However, two recent clinical trials (NCT01800695 and NCT02343406) have reported that ABT-414 monotherapy caused frequent ocular toxicities, such that the effect of ABT-414 warrants further study.[22],[23] EGFRvIII rearrangement vaccines, such as rindopepimut vaccine (CDX-100), are also under clinical trials.[24] However, a recent international phase III trial with 745 enrolled newly diagnosed EGFRvIII expressing GBM patients in 22 countries showed that CDX-110 could not significantly improve the median OS of patients as compared to the patients treated with TMZ alone (NCT01480479).[25] These unsatisfactory results may be due to the existence of blood–brain barrier (BBB) and the pharmaceutical properties. The more effective delivery system or combination therapy with CDX-110 may need. Adeno-associated virus vector loaded with cetuximab (AAVrh. 10Cetmab) can bypass BBB, directly deliver to CNS locally and sustainably, and therefore may decrease the tumor volume and prolong survival.[26]

Human EGFR 2 (HER2, also known as ERBB2), which belongs to the EGFR family, is an important prognostic factor for breast cancer. Its expression has also been confirmed in approximately 80% GBM primary cell lines,[27] and upregulated expression levels are related to low survival rates in 41% GBM samples.[28] HER2 has also been found in other malignancies, including ovarian tumors, colon carcinoma, and nonsmall cell lung cancer. HER2 oncogene-encoded transmembrane glycoprotein regulates tumor angiogenesis mainly through its tyrosine-specific kinase activity; however, the immunogenicity and regulation mechanism in GBM are unclear. HER2-specific vaccines, peptides, and cytotoxic T-lymphocytes (CTLs) have been developed and tested in clinical trials for breast cancer, but HER2 as a tumor-associated antigen utilized for targeted and immunotherapy for GBM needs further exploration. HER2-specific chimeric antigen receptor T (CAR-T) cells therapy has achieved some positive results in GBM models. HER2-specific T-cells generated from GBM patients can secrete immunostimulatory cytokines, such as interferon (IFN)-γ and interleukin (IL)-2, that can kill HER2-positive GBM stem cells and CD133+ stem cells in xenogeneic severe combined immunodeficiency GBM models.[29] Recently, Zhang et al.[28] demonstrated the cell-killing capability of HER2-specific natural killer (NK) cells, NK-92/5.28.Z-cells, in HER2-positive murine GBM tumors. NK-92/5.28.Z-cells were genetically modified NK-92 single cell clones expressing CAR with high-affinity to HER2. CAR NK cells for a new phase I clinical trial are in preparation.

Vascular endothelial growth factor pathway

Angiogenesis is a distinct pathological feature of GBM, which is attributed to high levels of VEGF, especially VEGF-A, which is hardly expressed in normal tissue. Therefore, antiangiogenic drugs, especially drugs against the VEGF signaling pathway, are ideal targets for GBM treatment. The VEGF receptor-targeted TKI BEV can specifically antagonize VEGF to reduce angiogenesis and tumor growth. The avastin in GBM study (BO21990) postevent subgroup analysis showed that OS of GBM patients with citrate dehydrogenase isoenzyme (IDH) wild-type extended to 4.3 months after BEV treatment.[30] However, a variety of antiangiogenic drugs, such as cediranib and cilengitide which inhibit VEGF RTK and integrin separately, have not shown improvement of OS of patients with GBM in phase III clinical trials. A phase III study is currently underway to evaluate the superiority of combined treatment with BEV plus dose-dense TMZ (ddTMZ) compared to monotherapy with BEV in ddTMZ in the first recurrent GBM. The result showed acceptable safety and pharmacokinetics, but the efficacy needs to be further studied (NCT02573324). The WHO clearly divided GBM into IDH wild-type and IDH mutant according to the phenotype in 2016. A phase III clinical study to investigate the efficiency of BEV for newly diagnosed GBM patients according to IDH phenotype is ongoing; the prospective study results may be a surprise.

Cytokines

Colony-stimulating factor (CSF)-1 plays a role in the proliferation and differentiation of macrophages through the CSF-1 receptor (CSF-1R). Coniglio et al.[31] found that the CSF-1 secreted by GBMs could promote the invasion of microglia, which stimulated the invasion of GBM completely depending on the CSF-1R signal. Animal experiments have shown that the penetration and infiltration of GBM are significantly reduced in the group using the CSF-1R inhibitor PLX3397.[32] Similarly, another CSF-1R inhibitor, BLZ945, also showed excellent inhibitory effects in glioma growth and progression by targeting macrophages.[33]

IL-10, an immunosuppressive cytokine involved in the inhibition of immune response, can inhibit the antigen-presenting function of macrophages and dendritic cells (DCs). IL-10-mediated anti-inflammatory properties are mainly regulated by transcription factor signaling. High levels of IL-10 produced by tumor cells play an autocrine and paracrine role in GBM transformation from low-grade to high-grade. Interestingly, the IL-10 viral homolog Cytomegalovirus (CMV) has been found in some patients with glioma and shown to influence the tumor microenvironment by upregulation of transforming growth factor-β (TGF-β) and VEGF.[34]

TGF-β is a newly found superfamily that promotes epithelial–mesenchymal transition and invasion and inhibits the immune response in tumor cells. In GBM, the TGF-β signal is positively regulated, which stimulates the migration and invasion of GBM cell lines. Compared to the original tumor cells, the expression of TGF-β and TGF-β receptor (TGF-βR) has been shown to be increased in CD133+ cells isolated from GL-261 cells (glioma cell line).[35] Interferingly, the expression of TGF-βR by small-interfering RNA or TGF-β-blocking agents will block the TGF-β signal, thereby completely blocking the migration of GBM. Further, a study found that the silencing of TGF-β-binding protein, LTBP4, leads to suppressed TGF-β activity and decreased proliferation in GBM cells. All these highlight the importance of TGF-β pathway in GBM-targeted therapy.[36] Currently, antisense oligonucleotide drug AP12009 targeting TGF-β pathway has achieved promising results in clinical trials.[37] Targeted treatments with granulocyte macrophage-CSF (GM-CSF), IL-2, IL-4, and multiple other important tumor-secreted cytokines are all effective approaches.

Cytomegalovirus

Human CMV (HCMV), which belongs to the herpesvirus family and infects people of all ages, has been found in variant tumors including colorectal cancer, prostatic cancer, and intracranial tumors.[38] The CMV gene early-expressed product, immediate-early 1, and late protein, phosphoprotein 65 (pp65), have been identified to be overexpressed in 50%–100% of GBM patients, but not expressed in the adjacent normal brain tissues. This provides a great opportunity to use the CMV antigens as potential GBM-specific therapeutic targets; however, detecting the presence of CMV in GBM patients is still a tremendous challenge.[39] The mechanism used by CMV to promote the growth of glioma and survival has been proved in vitro, where CMV can (1) increase cell stemness and migration,[40] (2) influence several critical signaling pathways including PDGFRα,[41] PI3K/AKT,[42] and TGF-β,[43] and (3) upregulate expression of cytokines such as IL-6, IL-8, and IL-10.[44] Anti-HCMV drugs (e.g., valganciclovir, cidofovir) and vaccinations (i.e., DCs admixed with CMV pp65 mRNA and GM-CSF) have showed prolonged OS and PFS (NCT00639639).[45]

Other target therapeutic markers

The methylation level of O 6-methylguanine–DNA methyltransferase(MGMT, a DNA repair enzyme) promoter is closely related to GBM therapy. MGMT methylation indicates longer survival, and lower expression of MGMT predicts significantly better prognosis in recurrent GBM.[36] Over the last years, two clinical trials on MGMT promoter methylation status in GBM have been ongoing (NCT02152982 and NCT02617589). IL-13 receptor subunit alpha-2 (IL13Rα2) is a highly overexpressed membrane-bound protein in more than half of adult glioma brains [46] and has been identified as a glioma-specific antigen.[47] Kim et al.[48] generated an antibody named scFv47 that can bind to IL13Rα2 with high affinity and specificity, showing promise for scFv47-modified exosomes and OVs for IL13Rα2-positive GBM and other malignant tumor treatment. The mechanisms of IL13Ra2-mediated signaling have been identified. Scaffold protein FAM120A was a signaling partner of IL13Rα2, which can activate PI3K/AKT/mTOR pathways.[49] FAM120A may be a key molecular target to IL13Ra2-specific therapy. Survivin (BIRC5), as a new member of the antiapoptotic protein family specifically expressed in tumors and embryonic tissue, was detectable in 85% of Grade IV glioma (GBM) specimens. Plasma of glioma patients derived exosomes with strong immunosuppressive activity hold promise as potential clinical biomarkers. Tumor plasma samples before-and-after vaccination-derived exosomes containing survivin and multiple other glioma progression-related genes (e.g., VEGF, IL-10, IL-6, IL1a, IL-12a, IL-8, IDH1, programmed cell death protein 1 [PD-1], PD-L1, TGF-β, and APOE) were useful in testing immunotherapy response.[50] The survivin peptide SVN53–67 (SurVaxM) can enhance T-cell activation and antitumor response. Currently, SurVaxM plus standard therapy enrolled newly diagnosed GBM patients is going on phase II clinical trial.[51]

More target therapeutic markers such as tyrosine-related protein 2 (TRP-2), glycoprotein 100 (gp100), IFN-inducible protein (absent in melanoma 2, AIM-2), and melanoma-associated antigen 1 (MAGE-1),[52] as well as other agents need to be found for this deadly disease. Multiple targeted agents, including EORTC 26101 and NovoTTF, have been on phase III clinical trials but unfortunately have not shown any improvement in OS of GBM patients.[53] Due to the existence of BBB, obtaining effective drug concentrations and understanding immune cells infiltration have become especially difficult.[54] Effective drug delivery approaches need to be developed in GBM therapy, such as nanoparticles or exosomes carrying and modifying conventional drugs to increase delivery efficiency.[55] Cisplatin (Cis) is clinically used in the treatment of multiple cancers with effective anticancer effects. Gold nanoparticles (GNPs) with tunable sizes and shapes can enter tumor cells to facilitate cancer diagnosis therapy, but their transferring abilities are prohibited by intact BBB. Recently, a novel strategy using GNP-bound Cis with a magnetic resonance-guided focused ultrasound delivery system has been shown to increase BBB permeability, improve drug biocompatibility, alter biodistribution, and enhance tumor inhibition.[56]


  Immunotherapy for Glioblastoma Top


Conventionally, the CNS was considered to be separated from other tissues by the BBB and the absence of DC and lymphatic system that all made it possible for brain to be immune privilege. However, this was proven wrong by many studies. Microglias have been found to have the function of antigen-presenting cells (APCs) and the existence of lymphatic vessels in the CNS have been discovered in recent years.[57],[58] Immature T-cells can obtain antigens from the CNS in the cervical lymph nodes and nasal mucosa via cerebrospinal fluid reflux,[59] and activated T-lymphocytes can penetrate through the BBB and play cytotoxic and regulatory functions.[60] This suggests that immunity exists in brain tumors. Tumor immunotherapies, including adoptive cell therapy, tumor vaccines, and immune checkpoint blockers, lay a solid foundation for GBM treatment. Immunotherapy is the direction of adjuvant therapy for glioma in the future.[61]

Adoptive T-cell therapy

Adoptive T-cell therapy (ATCT) delivers activated tumor-specific T-cellsin vitro to patients and is one of the active fields in the study of tumor biotherapy. CAR-T cells therapy is a new and developing T-cell immunotherapy, which has emerged in GBM immunotherapy. CAR-modified T-cells are genetically produced by introducing fusion genes of single-chain antibody, costimulatory molecules, and immune receptor tyrosine activating motif into T-cells. Compared with normal T-cells, CAR-T cells have the advantages of antigen recognition, high cytotoxicity, non-MHC restriction, and amplification in vivo. CD19-specific CARs were approved by the US FDA for acute lymphoblastic leukemia.[62] The antitumor effects of CAR-T cells against GBM have also been evaluated in many preclinical models,[63] and multiple CAR-T cell targeting GBM have been developed, including EGFRvIII, IL-13 receptor alpha 2 (IL13Rα2), HER2, erythropoietin-producing human type-A2 (EphA2), CD70, and CMV.[64]

Recent studies have shown that CAR-T cells targeting EGFRvIII play a role in the treatment of GBM,[65] and multiple trials are ongoing or being prepared.[66] A phase I study that enrolled 10 recurrent GBM patients demonstrated safety and feasibility by EGFRvIII CAR-T cell therapy.[67] However, a recent study demonstrated that there was no association between EGFRvIII status and OS in EGFR-amplified GBMs,[68] indicating that combined therapy with EGFRvIII needs to be investigated further on trials. IL13Rα2-CARs T-cells can produce cytokines, including IFNγ and TNF-α, and show cytolytic activity by creation of pro-inflammatory microenvironment in glioma-bearing mice.[69] A phase I trial for anti-IL13Rα2 CAR T-cells for recurrent GBM has already completed (NCT00730613) and has shown promising results.[70] Another IL13Rα2-targeted CAR-T cell therapy in a multifocal recurrent GBM patient also showed significant effects.[71] Ahmed et al.[72] reported a phase I study that enrolled 17 HER2+ GBM patients treated with HER2-specific CAR-modified virus-specific T-cells. It achieved safety, feasibility, and anti-GBM activity end points, and three phase I clinical trials are now underway (NCT03389230, NCT03383978, and NCT02442297). CAR-T cells targeting both HER2 and IL13Rα2 antigens showed enhanced antitumor activity in U87 and U373 transplantation models.[73] The results also showed overcoming immune escape and enhancing antitumor effects in GBM patients.[74] In addition, two-stage I/II clinical trials are ongoing for evaluating the antitumor response and acceptable safety of second-generation HER2 and the third-generation EGFRvIII-specific CAR-T cells for the therapy of relapsed GBM. EphA2, a member of the RTKs family, has been shown to be strongly overexpressed in GBM patients and regulates tumor initiation, migration, neovascularization, and angiogenesis.[63] CD70, belonging to TNF receptor family, was highly expressed in tumor cell lines. EphA2 and CD70 can be novel CAR-T cell targets for GBM.[75] A recent clinical trial in recurrent GBM patients has indicated promising clinical benefit of the ATCT using the CMV pp65-specific T-cells.[76]

Tumor vaccines

Many vaccines with the function of stimulating adaptive immune responses have been investigated for the GBM treatment.[77] Among them, DCs have been recognized as a potent APCin vivo and are commonly used vector for immunotherapy. DC vaccines have been found to increase the multifunctionality of tumor-specific CD8+ T-cellsin vivo and have a relationship to prolonged OS.[78] DC vaccine-based immunotherapy has been shown beneficial in both preclinical animal studies and clinical trials. Two studies that enrolled recurrent and newly diagnosed malignant glioma patients found that the median survival and 5-year survival were higher for the DC vaccines treatment group.[79],[80] The clinical efficacy of DC vaccine is affected by the tumor immunosuppression environment and tumor immune escape, which play key parts in regulating T-cells and myeloid-derived suppressor cells (MDSCs). Studies have found that STAT3 can regulate the response of GM-CSF-derived DCs to CpG, effectively inhibit MDSCs, and overcome tumor immunosuppression. STAT3-null DCs were better antigen presenters with more secretion of inflammatory cytokine.[81] Another study showed the potentially great therapeutic benefit of modified DC-based vaccine and tumor-derived exosomes in GBM treatment. Tumor-specific CTLs were activated in this vaccine to break the immune tolerance and improve the immunosuppressive environment.[82] The autologous tumor lysate (ATL)-pulsed DC vaccination combination with Toll-like receptor agonists also have been demonstrated and may be an auxiliary treatment for GBM patients. Another study found that immune-based therapy may be more effective for GBM with mesenchymal markers.[83] Glioma stem cells (GSCs) can be used as a potential antigen due to its own characteristics. Studies have shown safety of mRNA-transfected dendritic cells targeting GSCs in GBM patients and a successful prolongation of median survival.[84] Currently, numerous DC vaccine trials are underway, including phase II trials (NCT01280552, NCT01635283, and NCT01204684) and a third therapeutic vaccine. DCVaxL was tested on a phase III stage of clinical trial (NCT00045968), and another recent phase I trial showed increased median survival in treatment with ATL mixed with DCs than glioma-associated antigen-DCs.[85] ICT-107 (an autologous DC vaccine contains six GBM markers including HER2, TRP-2, gp100, MAGE-1, IL13Rα2, and AIM-2) is now being investigated in an ongoing phase III trial.

Heat shock protein (HSP), which is composed of tumor-associated antigens that can induce specific antitumor reactions and enhance the inflammatory response, produce an efficient tumor-specific immune response. The HSP–peptide complex-96 (HSPPC-96) vaccine is used more frequently in GBM. The phase I clinical trial completed by Crane et al.[86] has demonstrated that HSPPC-96 is safe and well tolerated in recurrent GBM treatment with no significant toxic and side effects. The test showed that peripheral blood and tumor microenvironment in 11 of 12 patients exhibited a potent immune response, with median survival up to 47 weeks.[86] In a single arm, nonrandomized phase II trial, 41 enrolled recurrent GBM patients received HSPPC-96 vaccine after surgery. The median survival was 42.6 weeks and the 6-month survival was 90.2%.[87] A more recent phase II trial showed safety profile and prolonged survival durations in 34/46 Grade I-II patients treated with HSPPC-96 plus TMZ (NCT00905060).[88] HSPPC-96 has been demonstrated to acquire promising and superior outcomes in phase I and II trials regarding recurrent GBM.[89]

Immune checkpoint inhibitors

Malignant tumors may inhibit the immune effector cells to eradicate tumors by an overexpression of immune ligands or receptors. Therefore, blocking the immune checkpoint including CTL antigen 4 (CTLA4), PD-1, and its receptor PD-L1 can be one of the most effective strategies for passively improving antitumor immunity.[90],[91] The combination of PD-L1 and PD-1 has been shown to participate in the pathogenesis and progression of glioma by inhibiting immune response of T-cells against cancerous cells in the GBM microenvironment. It has been proven that PD-L1 and PD-1 can be used as targets for immunotherapy in glioma.[92] Liu et al.[93] found that the presence of PD-L1 in 17 cases of GBM could be a negative prognosticator for survival. Blockade of the PD-1/PD-L1 antibodies can also effectively elicit the anti-tumor T-cell responses. In the past few years, PD-1/PD-L1 axis or CTLA4-targeted inhibitors have shown significant therapeutic effects in melanoma as well as in other cancer types. Recently, Zhang et al.[94] found that CD4/6 (a cell cycle kinase) inhibitors can improve the therapeutic effect of immunologic checkpoint inhibitors, by increasing the expression of PD-L1. An increasing number of clinical trials are ongoing since 2011 to evaluate the potential therapeutic efficacy of PD-1/PD-L1 inhibitors, including nivolumab, pembrolizumab, pidilizumab (anti-PD-1), and MEDI4736, MPDL3280A (anti-PD-L1) as monotherapies and combination therapies for GBMs. There are still two ongoing clinical trials to investigate the nivolumab, TMZ, and radiation therapy or their combination for newly diagnosed patients with GBM (NCT02617589, NCT02667587) [Table 1]. The combination of ipilimumab (anti-CTLA-4) and nivolumab was tested in a phase III randomized trial in recurrent GBM (CheckMate 143, NCT02017717)[95] but completed with an disappointing end point without raising improved OS compared with BEV monotherapy, indicating that combination immunotherapy including these immune checkpoint inhibitors and targeted therapy may be necessary to enhance curative effects.
Table 1: The ongoing Phase III clinical trials of targeted therapy or combination treatment in glioblastoma (Ref: https://clinicaltrials.gov)

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  Gene Therapy Top


Gene therapy attempts to kill cancer cells by the activation of immune response, using adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir system (HSV-Tk/GCV) containing tumor-suppressor genes. The mutation of antioncogene p53 occurs in 31.55% of the GBM patients according to the TCGA data. The combined delivery of p53 and HSV-Tk/GCV can cause tumor cell apoptosis and induce the “suicide” of tumor cells by metabolic changes, respectively.[96] Recently, Chow et al.[97] developed a novel approach to screen gliomagenesis suppressors in mice. More concretely, they delivered frequently mutated genes including p53 into the brains of mice by adeno-associated virus-mediated clustered, regularly interspaced, short, palindromic repeat to drive tumorigenesis. The discovery of more functional tumor suppressors will be more conducive to gene therapy for GBM.

Another gene therapy approach for glioma treatment is to deliver enzymes/drugs such as cytosine deaminase, carboxylesterases, and 5-fluorocytosine (prodrug of 5-fluorouracil) to local tumor sites in the brain through neural stem cells (NSCs) and other cell types which can migrate toward neoplastic lesions. Currently, two NSC-based clinical trials in relapsed HGG are ongoing (NCT02192359 and NCT02015819). NSC-based gene therapy has been expected to have a tremendous therapeutic effect in clinical trials as NSC can be modified to deliver variant antitumor agents (i.e., toxins, cytokines, OVs, nanoparticles, antibodies) tumor-locally, safely, and productively.[98]


  Oncolytic Virotherapy Top


OVs with active vitality can improve antitumor response via pathogen-associated molecular patterns. As a result, oncolytic virotherapy will be a potential method to destruct the immunosuppression of GBM.[99] Engineered attenuated viruses can safely and selectively infect and lyse the tumor cells without harm to normal tissue.[100] Multiple modified viruses, including retrovirus, measles virus, poliovirus,[101] HSVs, and adenoviruses, have been evaluated in oncolytic viral treatment for GBM, and some are already on clinical trials. Toca 551 (vocimagene amiretrorepvec) is a replicating retrovirus that can integrate into the DNA genome of tumor cells. A combined therapy of Toca 511 and Toca FC has already begun clinical trial in newly diagnosed or recurrent HGG (NCT02598011 and NCT02414165).[102] PVSRIPO, a recombinant oncolytic poliovirus, is ongoing phase I study (NCT01491893) and has been designated as breakthrough status by the FDA. Several HSVs including G207, M032, G47Δ, and HSV1716 are ready for large-scale GBM trials to bring new hope for GBM patients.[103] Modified adenovirus delta-24-RGD (DNX-2401) and ONYX-015 (Ad5) and carcinoembryonic antigen (MVCEA) based on the measles virus also have been on clinical trials.[104] The combination therapy of OVs with immune checkpoint blockades has also been on study to evaluate enhanced immunostimulatory effect (NCT02798406).[105]


  Conclusion Top


Although there are a variety of treatment options for GBM, and it has been proven that targeting therapy and immunotherapy are safe and feasible, profoundly complex brain tumors themselves are faced with many difficulties, such as the lack of specific antigen, tumor immune escape, and adverse reactions. Single-drug targeted therapy only have modest results, and sometimes, while the results of animal experiments are promising, human trials are often unsatisfactory. In addition, the immune system gradually degenerates with age, and suppression of immune system by chemotherapy and radiotherapy and other factors make the target and immunotherapy greatly compromised. Nevertheless, we believe that GBM immunotherapy and targeted therapy will certainly shine in the near future. Further, the diagnosis and treatment of glioma by immunological methods or the use of tumor-infiltrating lymphocytes to judge prognosis, classify, and guide the treatment of brain tumor by immunological molecular characteristics are also main research directions of the future.

Researchers in the genome mapping program of cancer have redefined the new classification of glioma and opened up new insights into the clinical study of glioma drugs. Looking for biomarkers in tumor tissues or blood as a predictor of drug efficacy will become an important challenge, and drug local delivery and toxicity may also be the major limiting factors. Different therapeutic targets must be considered comprehensively in the new treatment strategy. The combination of targeted drugs has already emerged in glioma, and the discovery of new drugs with CNS penetration properties discovery needs to be expedited by high-throughput drug screening. The combined treatment of targeting therapy, immunotherapy, and cytokine therapy in hope to repress therapeutic resistance and reduce differential sensitivity is being actively researched. Reasonably designed critical trials are effective treatment approaches in precision medicine. For example, a phase II trial including chemotherapy (carmustine, paclitaxel cyclophosphamide and Cis, autologous tumour cell vaccine, cytokine therapy by GM-CSF, G-CSF, and IL-2 combined with autologous lymphocyte infusion) is ongoing (NCT00014573). Induction of antitumor immune responses by local delivery reagents, immunotherapy, and immune checkpoint drugs increases the availability and rationale for this combination strategy. Currently, multiple combination immunotherapies with stereotactic radiosurgery, local chemotherapy, immune checkpoint blockages, and oncolytic viral therapy are predicated on this paradigm (NCT01811992, NCT02197169, and NCT02311582). We expect the advances in immunology and their combination treatment to bring more surprise to antitumor targeting and immunotherapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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