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Table of Contents
Year : 2023  |  Volume : 6  |  Issue : 1  |  Page : 3-8

Current status of clinical application of immunotherapy in the treatment of glioma: A narrative review

1 Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), Chongqing, China
2 INSERM U 1191 – CNRS UMR 5203, University of Montpellier, Montpellier, France

Date of Submission30-Jan-2023
Date of Decision14-Mar-2023
Date of Acceptance15-Mar-2023
Date of Web Publication30-Mar-2023

Correspondence Address:
Prof. Jean-Philippe Hugnot
INSERM U 1191 – CNRS UMR 5203, Université de Montpellier, Montpellier 34094
Prof. Shengqing Lv
Department of Neurosurgery, Xinqiao Hospital, Third Military Medical University (Army Medical University), No. 183 Xinqiao Street, Shapingba District, Chongqing 400037
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_2_23

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Glioma is a common type of brain tumor. Current treatment for glioma includes surgical resection, radiotherapy, chemotherapy, and tumor-treating fields. The application of immunotherapy to treat glioma is still far from satisfactory in the clinic. Here, we review the mechanisms of immunotherapy for glioma (including immune checkpoint inhibitor, chimeric antigen receptor-T-cell, tumor vaccine, and oncolytic virus) and the results of completed clinical trials, and will discuss the current status of immunotherapy and possible future directions.

Keywords: Chimeric antigen receptor-T-cell, glioma, immune checkpoint inhibitor, oncolytic virus, tumor vaccine

How to cite this article:
Chen Q, Ren P, Huang G, Zhang Z, Hugnot JP, Lv S. Current status of clinical application of immunotherapy in the treatment of glioma: A narrative review. Glioma 2023;6:3-8

How to cite this URL:
Chen Q, Ren P, Huang G, Zhang Z, Hugnot JP, Lv S. Current status of clinical application of immunotherapy in the treatment of glioma: A narrative review. Glioma [serial online] 2023 [cited 2023 Nov 29];6:3-8. Available from: http://www.jglioma.com/text.asp?2023/6/1/3/372822

  Introduction Top

Glioma is the most common adult primary malignant brain tumor. Representing 6% of primary central nervous system tumors in adults, low-grade glioma typically has a more promising prognosis. GBMs have the worst prognosis and are most likely to cause death among all solid malignancies, with a median survival time of <2 years.[1] Magnetic resonance imaging (MRI) is the main and most accurate means to diagnose GBM, but the lack of obvious signs in the early stage often leads to the irreversibility of the disease when the patient is diagnosed. According to the 5th edition of the WHO Classification of Neoplasms of the Central Nervous System (WHO CNS5) – the first of these editions – there may be significant differences in the treatment criteria and prognosis of gliomas. Circumscribed gliomas are recommended for early excision and adjuvant chemotherapy if necessary, and the prognosis is usually good.[2] Diffuse gliomas and other high-grade gliomas are highly refractory depending on their molecular subtype and require chemotherapy.[2] However, in the case of GBM, feasible postexcisional radiotherapy plus temozolomide chemotherapy defines the current standard of care.[2]

The traditional view of the CNS as an “immune privileged” environment has been denied. In the intracranial immune system, immune cells and lymphatic drainage play an important role.[3] The flow of cerebrospinal fluid into the nasal and cervical lymph nodes of the body makes the intracranial immune system not isolated. Infiltrating immune cells in glioma consist mainly of macrophages, followed by lymphocytes, especially CD4+ and CD8+ T-lymphocytes. Notably, microglia and resident macrophages outnumber infiltrating T-cells in glioma, and the lack of T-cells in the tumor microenvironment contrasts with observations in other types of tumors such as melanoma or lung cancer.[4]

A complex series of mechanisms have evolved in the human immune system to inspect and eradicate cancer cells. The immune system tries to kill tumor cells by presenting tumor antigen to T-cells, activating T-cells, and playing an antitumor function.[5] These CD8+ cytotoxic T-lymphocytes migrate to tumor and infiltrate there, to recognize cancer cells, and to trigger tumor cell death. Then, the cancer cells recognized by T-cells release tumor-associated antigens and enhance the immune response cycle. During the cycle, signal regulation is carried out between immune cells and between immune cells and tumor cells through various ligand–receptor bindings. In these signals, the immune checkpoint signal controls the stimulation or inhibition of T-cells. However, tumor cells have the capacity for immune escape. Tumor immunotherapy is a treatment targeted to activate the body's own immune response to overcome the immune evasion of tumor cells.[6] Antibodies that block programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4 have been shown to have activity in many types of solid tumors and are now the standard treatment for advanced melanoma, non-small cell lung cancer, and more other malignant tumors.[7] In the case of melanoma, the presence and density of tumor-infiltrating lymphocytes affect the outcome of treatment and patient prognosis.[8] Special composition of immune cells in gliomas may be an obstacle to immunotherapy.[9] While over the past decade or so of relentless research and exploration into the treatment of glioma, numerous treatments have been proposed, since 2005, only three new therapies have been approved by the Food and Drug Administration for GBM: temozolomide, bevacizumab, and tumor-treating fields.[10] The application of immunotherapy for glioma treatment has not been fully recognized. Until now, immunotherapy has shown promise, but many challenges and obstacles remain in glioma.[11]

In this review, we provided an introduction of the latest researches and clinical trials on immunotherapy for glioma treatment including immune checkpoint inhibitor, chimeric antigen receptor (CAR)-T-cell, tumor vaccine, and oncolytic virus and to discuss the limitation and the prospect of the future directions of immunotherapy applied to treat glioma, aiming at providing a comprehensive summary of clinical trials according to the currently available literature for better application of immunotherapy for glioma treatment.

  Retrieval Strategy Top

Literature for this review was searched and obtained from the PubMed database. We searched literature using the following keywords: glioma, immune checkpoint inhibitor, CAR-T-cells, tumor vaccines, and oncolytic virus. Literature covered in this review (80% of all references) was published from 2016 to 2022. A publication of 1999 was included in consideration of its significance and relevance in the application of virus for glioma treatment.

  Immune Checkpoint Inhibitor Top

T-cell activation and response requires the major histocompatibility complex to present antigens to T-cells, and then checkpoint molecules determine whether T-cells are stimulated or inhibited. The following checkpoint molecules have been recognized as stimulatory or inhibitory: CD28, CD80, CD86, CD40 L, CD137, TNFRSF4 (also known as OX40), and CD58 promote immune activation, while cytotoxic T-lymphocyte-associated protein 4, PD1, lymphocyte activation gene 3, T-cell Ig and ITIM domains (TIGIT, also known as WUCAM, Vstm3, or VSIG9), and T-cell immunoglobulin and mucin domain-3 (TIM-3; also known as hepatitis A virus cellular receptor 2) suppress immune activation.[12] In melanoma and other types of solid tumor models, immune checkpoints have been found to be used by tumor cells to evade immune detection. Immune checkpoint inhibitor therapy has been applied for treatment of other solid tumors in the clinic. However, the exact function of most of these checkpoint molecules has not been demonstrated in glioma models.[13]

Clinical trials of immune checkpoint inhibitors in glioma have focused attention on pembrolizumab, nivolumab, and ipilimumab. A phase III clinical trial compared the efficacy, toxicity, and safety of treatment with bevacizumab and nivolumab (NCT02017717).[14] Nivolumab is a fully human immunoglobulin G4 monoclonal antibody targeting the programmed cell death protein 1 immune checkpoint receptor. Overall survival (OS) was comparable between the bevacizumab and nivolumab groups. The progression-free survival and objective response rate were better in the bevacizumab group based on the data. Durations of response were longer in the nivolumab group based on the data. Toxic effects were not different from the known safety profiles of nivolumab and bevacizumab. It suggests the possibility of immune checkpoint inhibitors for the treatment of glioma. In a phase I clinical trial, investigators used pembrolizumab (NCT02054806) to treat patients.[15] Pembrolizumab is a fully human monoclonal antibody targeting programmed cell death protein 1 immune checkpoint receptor. Pembrolizumab demonstrated sustained antitumor activity, but the effect of pembrolizumab could not be linked to receptor expression levels. In a phase I clinical trial (NCT02017717), investigators compared the efficacy and safety of the combination of ipilimumab and nivolumab.[16] Ipilimumab is a fully human monoclonal antibody targeting cytotoxic T-lymphocyte-associated protein 4 immune checkpoint receptor. Ipilimumab affects patient tolerance and has no positive indicators combined with nivolumab.[16] Overall, pembrolizumab, nivolumab, and ipilimumab demonstrated differences in survival, intensity, and duration of antitumor effects in clinical studies, but their therapeutic effects did not achieve expectations.

Immune checkpoint inhibitor therapy is less effective in treating glioma, so it is considered in combination with other treatments. The investigators treated recurrent GBM patients by hypofractionated stereotactic irradiation and pembrolizumab in a phase I clinical trial (NCT02313272).[17] Patients on triple therapy with hypofractionated stereotactic irradiation, pembrolizumab, and bevacizumab had improved survival (progression-free survival and OS) and did not exhibit significant toxic effects. It is worth exploring a combination of immune checkpoint inhibitor therapy with other therapies.

  Chimeric Antigen Receptor-T-cell Top

CARs are engineered fusion proteins. Following transfection of a CAR construct into autologous or allogeneic T-cells in peripheral blood using plasmid transfection, siRNA, or viral vector transduction, the T-cells are infused into the patient's body, targeting any tumor antigen exposed on surface and identified by the CAR's extracellular targeting moiety.[10] Primary T-cell activation occurs upon binding of CAR to its associated antigen, leading to cytokine release, cytolytic degranulation, and T-cell proliferation. In addition, T-cell effector mechanisms and memory responses also occur in a costimulatory-dependent manner.[18] Therefore, CAR-T-cells continue to produce immune response after binding with corresponding tumor-related antigen. In addition, one of the advantages of CAR-T-cell therapy is to play an antitumor role independently of the autoimmune system. Human epidermal growth factor receptor 2, epidermal growth factor receptor variant III (EGFRvIII), and interleukin-13 receptor alpha 2 (IL-13 Rα2), as the major candidates for the study of tumor-associated antigen targets of CAR-T-cells in glioma, they have been found that can be expressed by glioma stem cells.[10]

A clinical trial (NCT02209376) proved the safety of CART-EGFRvIII product for glioma treatment first. The researcher redirected single-dose autologous T-cells to EGFRvIII mutation through CAR and injected the patients with indications intravenously.[19] One patient required no further treatment for over 18 months following CART infusion. They found no marked tumor regression on MRI in any patient. However, the definitive conclusion about the clinical benefit and potential of CART EGFRvIII products will require larger cohorts.[19] A phase I clinical trial (NCT00730613) utilized a CAR construct, using autologous primary human CD8+ cytolytic T-lymphocytes targeting IL13Rα2 for the treatment of GBM.[20] The investigators demonstrated the safety of repeated intracranial administration clones of the IL13-zetakine+ CD8+ cytolytic T-lymphocyte lineage, and under continuous observation, some patients were found to have no adverse events and to have transient antitumor function.[21] CAR-T-cell therapy is faced with the problem of CAR-T-cell delivery to a designated site. Although no single strategy can allow CAR-T-cells to reach the tumor and enhance their antitumor function once there, a combination of individually targeted delivery combined with checkpoint molecular knockdown and cytokine stimulation should enable multi-stimulated and activated T-cells to persist and generate robust immune responses in a patient's body.[22]

  Tumor Antigen Vaccine Top

During tumor tumorigenesis, mutations caused by genetic instability typically arise in both noncoding and coding regions of the genome, where changes in DNA of the coding region include nonsynonymous mutations or single-nucleotide variants, mutational frameshifts, gene fusions, posttranslational modifications that alter the amino acid sequence, and intron retention.[23] The changes in amino acid sequence caused by these changes in DNA can result in short peptides that are not found in normal cells, and these short peptides are referred to as neoantigens. Some of these short peptides are transported to the endoplasmic reticulum and loaded on the major histocompatibility complex-I. The major histocompatibility complex-I which is loaded with peptides enters the cell membrane through the Golgi apparatus, thereby inducing antigen presentation and recognition by receptors on CD8+ T-cells and cytotoxic T-cells are activated and exert tumor-killing effects.

Tumor-associated antigen (TAA) is a protein expressed by unmutated genes that are significantly highly expressed in tumor cells but rarely expressed in normal cells.[24] Immune cells recognize these overexpressed proteins and activate the immune system response, thereby acting to kill tumor cells. However, targeting TAA can also lead to autoimmune toxicity since TAA is a normal host protein and is subject to immune tolerance. In contrast, neoantigens are only expressed in tumor cells but not in normal cells, including antigens produced by genome-integrated tumor viruses and antigens produced by mutant proteins. It is highly immunogenic and heterogeneous and is unaffected by central tolerance.[25] Moreover, targeting neoantigens is less likely to result in autoimmunity. Therefore, neoantigens are the preferred targets for tumor vaccines. Based on the epigenetic characteristics and immunogenicity of neoantigens, medications can be designed and synthesized to activate the immune system based on the mutation of the tumor cells, which results in antitumor effects.[26]

One of the most anticipated tumor vaccines is rindopepimut, formerly known as CDX-110, which targets EGFRvIII. The vaccine was investigated in a number of clinical trials. In a phase 3 ACT IV trial (NCT01480479), the investigators treated patients with EGFRvIII-positive GBM with rindopepimut in combination with radiotherapy and temozolomide, compared with radiotherapy and temozolomide alone. The result was negative. Rindopepimut did not improve survival.[27] Furthermore, the rindopepimut group did not show significant differences from the control group in terms of progression-free survival, tumor response, or quality of life measurements. Mutated isocitrate dehydrogenase 1 (IDH1) defines a molecularly distinct subtype of diffuse glioma.[28] A phase I clinical trial (NCT02454634) investigated the efficacy and the safety of the IDH1 R132H mutant peptide vaccine (NOA-16) in IDH1-mutated high-grade gliomas, which has been shown to lead to T-cell activation and humoral immune response.[29] Whether glioma development is associated with cytomegalovirus (CMV) infection is controversial, but CMV antigen is found overexpressed in glioma. The vaccine is based on CMV and targets pp6537, which is a major CMV structural protein. The safety of CMV pp6537 has been demonstrated. In a sequential clinical trial (NCT00639639) using CMV pp65 DC vaccines in newly diagnosed GBM patients consistently proved an improved OS.[30]

Given the potential for antigen evasion using a single-peptide vaccine, the most recent type of peptide vaccines was designed to have function synergistically with multiple tumor antigens. A phase II clinical trial showed that administration of the ICT-107 vaccine consisting of 6 TAAs (MAGE-1, HER-2, AIM-2, TRP-2, gp100, and IL13Rα2) pulsed in DC resulted in a notable improvement in the progression-free survival of GBM patients.[31]

  Oncolytic Viruses Top

Colombo et al.[32] completed a clinical trial using retroviruses as vectors for glioma in 1998. Despite the low efficiency of viral transduction and limited therapeutic scope, the team concluded that viral-based gene therapy technology could be used in early, well-defined cases of GBM recurrence. Viruses have been used in the treatment of gliomas for at least 20 years. However, immunotherapy with oncolytic viruses has been widely used in glioma clinical trials over the past 5 years.

Oncolytic viruses are artificially genetically engineered to specifically replicate in tumor cells and lyse tumor cells without harming normal cells. The goal of oncolytic virus immunotherapy is to transform the virus from a covert pathogen into a finely tuned therapeutic vector that can facilitate direct or indirect viral attack on cancer cells.[33] Oncolytic viruses have antitumor activity by especially replicating in and lysing tumor cell and the lysis products are immunogenic and trigger an immune response.

Lang et al.[34] conducted a phase I clinical trial using DNX-2401 (Delta-24-RGD; tasadenoturev) for the treatment of glioma. By modifying the E1A gene, the virus is only able to replicate in tumor cells with a malfunctioning Rb pathway. Eighteen of the 25 enrolled patients had a reduction in tumor size with a median OS time of 9.5 months, independent of dose. Remarkably, five patients survived more than 3 years, three of whom had a 95% reduction in an enhancing tumor cross-sectional area. There was no obvious sign of infection. The investigators concluded that DNX-2401 directly induces tumor oncolysis, then an antitumor immune response, and that tumor infection induced a decline in the expression level of TIM-3.[34] TIM-3 is an important checkpoint molecule that inhibits T-cell. Fares et al.[35] conducted a phase I clinical trial (NCT03072134) using NSC-CRAd-S-pk7, a modified oncolytic adenovirus that is delivered by neural stem cells. This is the first-in-human trial to test the delivery of an engineered oncolytic adenovirus to neural stem cells. Trial results demonstrated correlative antitumor activity. One of 12 patients had a partial response to therapy and 10 of 12 patients had stable disease.

In a phase I clinical trial, G207 was used for the treatment of recurrent GBM, which is a type 1 herpes simplex virus mutant.[36] G207 contains deletions in the two loci of the viral gene γ134.5 gene, in addition to a disabling lacZ insertion in UL39. A phase I clinical trial used modified reovirus to treat glioma.[37] Ten patients had stable disease, one had a partial response, and four had progressive disease. Another phase I clinical trial used ONYX-015 for the treatment of glioma.[38] ONYX-015 is an adenovirus mutant. There are evidence that ONYX-015 replicates specifically more efficiently in cells with abnormal p53 pathway. Twenty patients have died as a result of tumor progression, one died of nontumor-related events (ruptured intestine), and three are still alive. A phase I/II clinical trial used NDV-HUJ, the oncolytic HUJ strain of Newcastle disease virus for the treatment of glioma.[39] One of 12 patients improved at trial progression. A clinical trial (UMIN000015995) was run with G47Δ, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial GBM after radiation therapy and temozolomide.[40],[41] Within 2 years, 1 patient with adverse reactions and 18 patients without disease progression.

Importantly, the virus is immunogenic. In clinical trials, researchers need to regularly test the concentration of viral antigens and antibodies in a patient's peripheral blood to avoid causing adverse reactions. Different types of viruses were used in oncolytic therapy, but in terms of results, the most common adverse event was fever followed by vomiting, nausea, lymphocytopenia, and leukopenia.

  Limitation Top

This manuscript has some limitations. It reviews and summarizes the recent progression of immunotherapy for glioma treatment. However, it only discusses the completed clinical trials of immune checkpoint inhibitors, CAR-T-cells, tumor vaccines, and oncolytic virus and it does not summarize the status and progression of the processing clinical trials.

  Conclusion and Future Perspective Top

Immunotherapy has been applied to solid tumors with great effectiveness, but due to the high heterogeneity of gliomas and the specificity of the immune environment, immunotherapy has not demonstrated significant effects and is difficult to apply in glioma. The solutions are to overcome the immune escape of tumors from the root or by combining multiple therapies to overcome resistance. Understanding the immune response and escape mechanism of glioma and finding specific immunotherapy targets help to find the way to overcome the immune escape of tumors. At present, some researches have explained the immune escape mechanism and drug resistance mechanism of glioma: avoiding the activation of the immune system through the specific screening of escape immune cells; inhibiting immune system activity through checkpoint molecules; having the ability to avoid being cleared when the immune system is activated.[42] Clinical attempts have been made to overcome glioma drug resistance by combining immunotherapy multidrug combinations or with radiotherapy. With the attempts and explorations, clinical trials have shown good results.



Financial support and sponsorship

This work was supported by the grant (No. 81972360) from the National Nature Science Foundation of China and grant (No. CQYC20200303149) from Chongqing Talents Project.

Conflicts of interest

There are no conflicts of interest.

Editor note: SL is an Editorial Board member of Glioma. He was blinded from reviewing or making decisions on the manuscript. The article was subject to the journal's standard procedures, with peer review handled independently of this Editorial Board member and their research groups.

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