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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 3  |  Page : 90-98

Progress on TTFields combined with other therapies for glioblastoma treatment: A narrative review

Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, China

Date of Submission12-May-2022
Date of Decision20-Jun-2022
Date of Acceptance04-Jul-2022
Date of Web Publication13-Oct-2022

Correspondence Address:
Prof. Jian Duan
Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, Jiangxi Province
Dr. Jiang Xu
Department of Neurosurgery, The First Affiliated Hospital of Nanchang University, 17 Yong Wai Zheng Street, Nanchang, Jiangxi Province
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_12_22

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Glioma is the most common primary malignant tumor in the skull, and the current treatment remains a combination of surgery, radiotherapy (RT), and chemotherapy. Radiation therapy plays an important role in the treatment of glioma, and currently, surgical resection under molecular pathology guidance plus postoperative radiation therapy and chemotherapy is the standard treatment protocol for primary glioma, but its widespread use is limited by its radiotoxicity. Meanwhile, with the increasing development of new technologies in the medical field of tumor treatment electric fields, there has been some improvement in the treatment and prognosis of glioma. TTFields are a noninvasive anti-cancer modality consisting of low-intensity (1–3 V/cm), medium-frequency (100–300 kHz), alternating current electric fields delivered through an array of skin sensors to provide optimal coverage of the tumor site. TTFields target cancer cells through multiple mechanisms of action, including inhibition of proliferation, migration, and invasion, disruption of DNA repair and angiogenesis, antitumor effects, induction of apoptosis, and immunogenic cell death. TTFields alone have good efficacy against tumors, and with the gradual development of technologies such as immune and targeted therapies, TTFields are now more frequently studied in combination with chemotherapy, RT, immunotherapy, and immunotherapy. At present, the treatment methods of glioma include surgery, chemotherapy, RT, immunotherapy and targeted therapy. This article will summarize the research progress of TTFields combined with other therapies to provide a reference for the treatment of glioblastoma.

Keywords: Chemotherapy, glioma, immunotherapy, radiotherapy, targeted therapy, TTFields

How to cite this article:
Cao Y, Wu H, Tang B, Li M, Wan Y, Duan J, Xu J. Progress on TTFields combined with other therapies for glioblastoma treatment: A narrative review. Glioma 2022;5:90-8

How to cite this URL:
Cao Y, Wu H, Tang B, Li M, Wan Y, Duan J, Xu J. Progress on TTFields combined with other therapies for glioblastoma treatment: A narrative review. Glioma [serial online] 2022 [cited 2023 May 28];5:90-8. Available from: http://www.jglioma.com/text.asp?2022/5/3/90/358550

  Introduction Top

Glioma is the most prevalent malignant brain cancer in the central nervous system. In recent years, the current treatment of glioma is still mainly surgical and supplemented by radiotherapy (RT), but the survival rate is still low. Gliomas are tumors originating from glial cells and are common intracranial primary malignant tumors,[1] with high incidence, low cure rate, and poor prognosis. The increased incidence of primary central nervous system tumors in the general population (17.3% global increase between 1990 and 2016) may be due to an aging population.[2] Malignant gliomas include mesenchymal oligodendrogliomas, mesenchymal astrocytomas, mixed mesenchymal oligoastrocytomas, and glioblastomas (GBM).[3] Glioblastoma accounts for approximately 60%–70% of malignancies, and glioblastoma is more common in men.[4] According to the literature, the 5-year relative survival rate for malignancies of the central nervous system is 35.8%,[4] and the 5-year survival rate for gliomas is second only to pancreatic cancer and lung cancer. The current standard of care for patients with GBM includes maximal surgical resection followed by RT and chemotherapy with temozolomide (TMZ). However, even with this combination therapy, median overall survival (OS) is approximately 10–16 months, with <10% of patients surviving 5 years or more from diagnosis, with little improvement in the last 40 years.[5],[6] Since 2005, RT followed by maximum safe surgical resection with TMZ and adjuvant TMZ chemotherapy has become the standard treatment strategy for GBM.[7] Current treatments for glioblastoma include surgery, RT, chemotherapy, immunotherapy, targeted therapy, and TTField.

TTFields are gaining prominence in the medical field as a new noninvasive tumor treatment,[8],[9] which is a therapeutic device worn on the head, where an insulated electrode sheet is placed on the peripheral skin of the tumor growth site and a noninvasive transducer array generating low-intensity medium-frequency alternating electric fields is placed alternately in the local anatomical area of the tumor.[10] Moreover, the frequency of tumor electric field does not stimulate nerves or muscles and has almost no effect on the heart.[8] TP53 mutations have been found in both primary and secondary GBM[11] and have been shown through numerous studies to be a prognostic biomarker for cancer worthy of investigation.[12],[13] TTFields affect apoptosis in GBM through P53-dependent and P53-independent effects.[14] It has been experimentally demonstrated that TTFields affect apoptosis and immune response-related genes regardless of TP53 status.[15] Prior to TTFields, the standard of care for ndGBM (i.e. the Stupp protocol) consisted of maximum safe surgical resection of the tumor followed by RT plus concomitant TMZ and adjuvant maintenance of TMZ.[7],[16] The Stupp protocol increased the median OS to 14.6 months, and RT alone to 12 months.[7] This review will focus on recent progress of TTFields combined with other treatment strategies for the treatment of glioblastoma.

  Database Search Strategy Top

An electronic search of the literature was performed using the PubMed database. The following keyword combinations were used to initially select articles to be evaluated: Mechanism of action of TTFields; TTFields in combination with chemotherapy; recent advances in chemotherapy; TTFields and RT; advances in RT; TTFields and immunotherapy; advances in immunotherapy; TTFields and targeted therapies; advances in targeted therapies. The literature search strategy was as follows: Two synonymous phrases, i.e. (1) TTFields for tumor electric field therapy, were combined with (a) chemotherapy, (b) RT, (c) immunotherapy, and (d) targeted therapy, e.g. “TTFields in combination with chemotherapy,” i.e. (1) + (a); “TTFields in combination with radiotherapy,” i. e., (1) + (b); and so on. The selected studies were published between 1999 and 2022. Participants were men and women of any age with a clinical diagnosis of glioma. The data extraction process focused on information about each study type and co-existing TTFields.

  Action Mechanism of Ttfields Top

Disruption of mitosis in cells

Kirson et al.[17] and Schwartz and Onuselogu[18] found that tumor electric field therapy interferes with the formation of glial cell spindle fibers through low-intensity, medium-frequency alternating electric fields, which prolongs cell mitosis and leads to apoptosis. TTFields can exert a destructive force on the formation of a spindle during mitosis, which can stop the division and eventually cause the death of cancer cells. Because TTFields are highly specific for rapidly replicating cancer cells, rapidly dividing cancer cell components are strongly attracted to alternating electric fields, which drive cell division and lead to incomplete mitosis and apoptosis.[19] In addition, TTFields inhibit the formation of mitotic spindle microtubules and prolong the mitotic process, i.e. the division of tumor cells,[16],[17] while intracellular proteins are rearranged due to the presence of electric fields[20] without leading to direct destruction of tumor cells, as not all cells are affected by mitotic spindle formation.[21] One study found that TTFieids have the ability to inhibit glioma cell division and replication by affecting spindle formation, both in in vitro cellular experiments and in vivo tests in tumor patients.[17]

Inhibition of tumor cell migration and invasion

When Kirson et al.[22] treated melanoma mice with TTF and rabbits with VX-2 squamous carcinoma, experimental results showed a substantial reduction in the number of metastases in the lung, limiting the spread of tumor cells, along with a longer survival of the animals. Another study demonstrated that TTFields inhibit glioblastoma migration and play an important role in invasive migration-related pathways, such as mitogen-activated protein kinase and nuclear factor-kappa B.[23] TTFields also affect microtubule dynamics, especially related to cell invasion and migration. TTFields, by inhibiting microtubule formation lead to a decrease in tumor cell motility, invasion, and migration.[23] In addition, it can also induce autophagy in glial cells and affect the migration of tumor cells.[24]

Inhibition of angiogenesis

In one study, 17 mice with melanoma were subjected to an electric field that stimulated tumor apoptosis and cell necrosis, and no recurrence or metastasis occurred in the mice after 4 months of observation. The main mechanism of action leading to apoptosis in this tumor was found to be a 93% reduction in microvessel density in the experimental group compared to the control group, which largely reduced the blood supply to the tumor tissue, and this method was efficient, without adverse effects and left only a slight scar.[25] Some researchers exposed HeLa cells and human umbilical vein endothelial cells suspensions to electric fields of 200, 400 and 600 kV/cm, respectively, and showed that electric fields could directly inhibit the angiogenesis of HeLa cells and human umbilical vein endothelial cells. It can induce apoptosis and necrosis, and play an anti-angiogenesis role.[26]

Inhibition of DNA repair

TTFields mainly affect cytoplasmic proteins but also affect the genomic integrity of cells.[27] In a range of non-small cell lung cancer cell lines, TTfields resulted in reduced DNA double-strand break repair due to downregulation of BRCA1 signaling, with some cell lines (H157 and H4006) being more sensitive than others (A549, H1650, and H1299).[28] Gene expression analysis showed a reduction in the expression of mitotically important regulators and replication stress genes under the effect of TTFields.[26] When TTFields and ionizing radiation (IR) were simultaneously applied to glioma cell lines (U118 and LN18), it resulted in delayed DNA damage repair.[29]

Activation of immune microenvironment

Tumor electric field treatment can furthermore have the ability to induce a stress response in the body and activate immune-mediated or death pathways.[30],[31] Activation of the immune system is another important mechanism of TTFields. Numerous preclinical trials have demonstrated that TTFields induce immunogenic death of tumor cells, and this effect is enhanced by combined anti-PD-1 therapy.[32] This synergistic effect is mediated through the expression of calreticulin on the tumor cell surface and the entry of secreted signals into the tumor microenvironment in HMGB1.[33] Evidence supporting immune activation suggests that implantation of rabbit kidney cells (VX-2) into the envelope and application of TTFields to the kidney resulted in a reduction in the number of lung metastases in these animals,[20] a phenomenon similar to the known distal effect of IR.[22]

Increase the permeability of cell membrane

Biofluorescence imaging showed that TTFields treatment of glioma cells (U87) for 6 h increased their uptake of a fusion protein of 5-aminolevulinic acid and firefly luciferase. Scanning electron microscopy also showed an increase in the number and size of membrane pores. The induced increase in membrane pore size is capped, allowing diffusion of only proteins with a maximum molecular weight of 40 kDa. This process is also reversible up to 24 h after the termination of TTFields.[24] It was also found that TTFields increased membrane permeability in glioma cells, which better illustrates the synergistic effect between TTFields and chemotherapeutic agents.[34]

Induction of cellular autophagy

One of the mechanisms of programmed cell death is “autophagic programmed cell death.”[35] It slows down stress by removing proteins and organelles that are harmful to the cell.[36] TTFields were shown to induce GBM autophagy through inhibition of the Akt2/mTOR/p70S6K axis by miRNA array studies, and treatment with 3MA + TTF versus TTF alone was also investigated, showing that (3-methyladenine, an inhibitor of autophagy) 3MA + TTF reduced tumor cell apoptosis, and studies showed that inhibition of autophagy attenuated the anticancer effects of TTF.[37] Akt2 has been reported to be associated with IR resistance.[38] Treatment of glioblastoma stem cells (GSCs) with TTF and IR, respectively, showed that Akt2 expression was reduced in TTF-treated GSCs and enhanced autophagic cell death in glioma stem cells.[39]

TTFields in the Clinic

In 2003, TTField was first used in six advanced or metastatic malignancies that were treated continuously for 14 days, showing a partial response to treatment of skin metastases in one primary breast cancer, cessation of tumor growth in three patients, no progression in one, and regression of peritumor lesions with peripheral growth initiation in another, and these patients tolerated TTField well.[40] In 2012, a study selected 20 cases of GBM, half with recurrent GBM and the other half with newly diagnosed GBM, who were also given TTFields, and 20% survived after 7 years, and these patients had no new tumor progression.[41] Some of the patients treated with tumor electric field therapy had rash-related adverse effects. In a phase III clinical trial of GBM conducted in 2006, 117 of 237 GBM patients received electric field therapy and the remainder received standard chemotherapy. The results of the trial showed that the median survival of patients treated with tumor electric field therapy alone and chemotherapy alone was 6.6 months and 6.0 months, respectively, suggesting that the results of TTFields were approved by the FDA in 2011 for the treatment of RGBM.[42] In 2017, it was reported in the literature that tumor electric field therapy was successfully used in a 13-year-old child with glioblastoma, and TTFields limited the recurrent growth of the tumor with no significant adverse effects.[43] In the same year, Green et al. applied TTField to five children with high-grade glioma and found that all five patients tolerated TTField well with no significant toxic side effects.[44] In a phase III trial of TTFields in GBM in 2015, the combination of TTFields with TMZ and TMZ alone significantly improved the OS of patients.[45] Later in 2020, TTFields were introduced into China. It was also found that craniectomy could be targeted in combination with TTFields to enhance the induced electric field in the underlying tumor tissue. For superficial tumors, a standard skull bone flap can be removed by craniotomy to increase the electric field intensity within the tumor by 60%–70%.[46]

  Limitations of TTFields Top

In 2020, tumor electric field therapy was formally introduced into China, as a new technology, tumor electric field therapy has some limitations: (1) In the related 11029 cases of tumor electric field therapy, the main side effect is contact dermatitis due to direct contact between electrode patch and patient's skin, mostly grade 1–2, without therefore terminating the treatment,[47] which can be relieved by local skin cleaning, application of antibiotics and other treatments. In order to improve the treatment effect, the electrode piece should be close to the skin of the head, which requires the patient to keep the hair shaved, and the tumor electric field treatment is not fully improved by one treatment. (2) In clinical trials, it is shown that TTFields only slow down tumor growth, not completely kill tumor cells.[48],[49] (3) The specific mechanism of action of tumor electric field therapy is not fully understood. (4) Tumor electric field therapy equipment is complex, with large weight and volume, and patients need to wear it continuously for more than 18 h/day during treatment, which is not conducive to the free movement of patients, which makes the patient's compliance decreased. This makes the patient's compliance less and requires a professional operation. (5) The treatment has not yet been applied to patients with cranial defects, and it is unknown whether it has any effect on pregnant women. (6) TTFields, as a novel treatment or new technology, are extremely expensive to treat, which to some extent limits their widespread use in clinical practice.[50],[51]

  Summary and Recent Progress of TTFields Combined With Other Treatment Strategies Top

TTFields combined with radiation therapy

Gliomas are currently treated mainly by surgery, with postoperative adjuvant RT and other comprehensive treatments.[43] Gliomas are aggressive and diffusely infiltrative, so they are prone to recurrence and are likely to lead to rapid tumor spread to other areas if they are not cleanly resected surgically.[52] There is no consensus on postoperative RT for low-grade gliomas, and high-grade gliomas are recommended to receive RT as early as possible after surgery, and the early or late RT can affect the survival time of patients.[53] Patients with glioma will have symptoms associated with headache, seizures, and hemiparesis, while patients' cognition, visual field deficits, and hemiparesis become more severe as the tumor increases.[54] It has been reported that when TTFields were used in combination with RT, TTFields were able to affect DNA fragment orientation, similar to disrupting microtubules, etc., affecting DNA repair,[17],[55],[56],[57] and although the markers of DNA repair, Rt51, and γ-H2AX, were upregulated, DNA repair received limitations due to their low cell viability.[58],[59],[60] Kim et al.[39] showed that TTF and IR have similar effects on cells, and the application of TTFields before RT showed that TTF and IR treatment synergize cell death and DNA damage, and synergistically inhibit cell invasion and migration. Giladi et al.[61] studied the application of electric field therapy after RT and found that tumor electric field therapy can block homologous recombination repair in irradiated cells affecting DNA damage repair and can serve to enhance the efficacy of RT for glioma. Karanam et al.[62] showed that TTFields combined with RT could inhibit DNA damage repair and enhance the sensitivity of RT to glioma cells. One study found that by testing the effect of applying TTField after radiation therapy causing DNA damage in U-118 MG and LN-18 glioma cells, it was concluded that the application of TTField after RT could inhibit DNA damage repair, thus slowing down the recurrence of glioma[61] and improving the progression-free survival and OS of patients. In animal tests, no additional skin reactions occurred in rats during RT due to the placement of transducers on the skin, which implies that TTField does not cause skin toxic reactions when administered during RT.[61] Taken together, the studies suggest that TTFields can increase the efficacy of RT. Some findings suggest that the placement of TTFields arrays does not interfere with the target volume coverage of radiation therapy. The effect of TTFields on the target volume was investigated by simulating the radiation schedule on a cranial model using TTFields to optimize the anatomy of the model.[63] Tumor electric field therapy plays an important role in synergistic RT, but the mechanism of action, safety, and adverse effects of tumor electric field therapy in synergistic radiation therapy urgently need more in-depth studies.

Differences between TTFields and radiotherapy

TTFields are applied using low intensity (1–3 V/cm) and moderate frequency (100–300 kH) AC electric fields acting through insulated electrode sheets placed in the local skin area of the tumor.[10] There are many core and septal proteins in cancer cell division that are susceptible to electric fields. TTFields disrupt mitosis in cancer cells, impede the synthesis of α-microtubule proteins at mid and late cell division, can disrupt and block microtubule formation, prevent spindle formation, prevent mitosis, and induce apoptosis.[64] TTFields may also interfere with the localization of septal proteins. TTFields did not disrupt the mid-cell cycle progression. The disruption occurs mainly between the end of the mid-phase and the beginning of the late phase of the cell cycle, and the late spindle contains important proteins whose purpose is to activate the cytokines Septin2, Septin6, and Septin7 complexes (heterotrimers), which are critical for structural stability and efficient cell separation during the formation of the cell kinetic oval groove.[58] When the spacer protein localization to the spindle is impaired, the process of oval groove formation is disturbed and cannot resist the hydrostatic pressure of the oval groove, thus causing membrane blistering and rupture. The cell rupture is followed by abnormal nucleation and overstimulation and the production of markers of immunogenic apoptosis.[56] The above belongs to direct mechanisms of action, and there are also indirect mechanisms of action, including inhibition of DNA repair, tumor cell migration, invasion, and angiogenesis, increased permeability of tumor cell membranes, and activation of the immune microenvironment.[65]

The mechanism of action of RT is to kill tumor cells directly by radiation and induce programmed death of tumor cells, which serves to assist in the treatment or cure of the disease. Breen et al.[66] found that high-dose RT did not prolong the survival time of glioma patients. Radiotherapy can cause chronic, acute, and subacute brain injury of varying degrees, and acute and subacute radiation brain injury can be ameliorated by glucocorticoid-like drugs. Acute brain injury can cause symptoms of cranial hypertension, subacute brain injury can cause fatigue, and advanced stages may cause progressive and irreversible brain tissue damage. Brain tissue damage from irradiation can be reduced using a reasonable total radiation dose and split-dose and corresponding target area.[67]

Bevacizumab is a monoclonal antibody targeting vascular endothelial growth factor, which can inhibit tumor angiogenesis; TMZ is an imidazolium derivative, which can easily cross the blood-brain barrier and can act on tumor cells at all stages of cell division, while TMZ has a sensitizing effect on RT.[68] One study showed that bevacizumab in combination with RT and TMZ was effective in treating recurrent malignant glioma, prolonging patient survival and with tolerable toxicity.[69] In a phase II randomized trial of 1205 patients, scholars divided 182 patients with recurrent GBM into two groups: A combination of stereotactic RT and bevacizumab and bevacizumab alone, and the median survival time was 10.1 months for patients treated with the combination and 9.7 months for those receiving bevacizumab alone, demonstrating that the combination was well tolerated.[70]

TTFields in combination with chemotherapy

Chemotherapy plays a crucial role in both preoperative and postoperative glioma. As most GBM patients develop chemoresistance during chemotherapy, the development of tumor resistance causes chemotherapy failure. Glioma drug resistance is mainly associated with heterogeneity, hypermutation, immune escape, and selective tumor splicing. TMZ is currently the main chemotherapeutic agent for glioma, and one study found that with TMZ treatment alone, TTFields improved the sensitivity of TMZ[22] and significantly improved progression-free survival and OS of tumor patients.[45] TMZ, compared with conventional chemotherapeutic agents, has a cell less toxic, with a bioavailability close to 100% and good tolerability.[71] The combination of TTFields can improve the 5-year OS of tumor patients.[72] TMZ can synergistically exert anti-tumor effects, and TTFields prevent mitosis of cells and synergistically enhance apoptosis by enhancing oncogene expression and regulating the mechanism of reactive oxygen species, thus increasing the sensitivity of TTFields to chemotherapy.[73],[74] Huse et al.[75] and Castañeda et al.[76] found that surgical resection of tumors followed by RT followed by TTFields + TMZ treatment prolonged progression-free survival and OS of patients. It has also been shown that TTFields can increase the blood-brain barrier permeability of chemotherapeutic agents in tumor cells. In an interim analysis of 315 glioma patients who had completed standard RT, 210 glioma patients were treated with TTFields + TMZ and 105 with TMZ alone, showing a median progression-free survival of 7.1 months for patients treated with the combination compared to 4.0 months for those treated alone, and median OS of 20.5 months and 15.6 months, the study suggests that early completion of The addition of TTFields in patients treated with standard RT prolonged progression-free survival and OS, and patients treated with TTFields in this study had a high incidence of local skin toxicity.[45] In a phase III trial of 695 patients with supratentorial GBM, divided into two groups treated with TMZ and combination therapy, the results of the study showed that the median progression-free survival and median OS were 4.0 months and 16.0 months for TMZ treatment compared with 6.7 months and 20.9 months for combination therapy, which showed that combination therapy significantly prolonged the intermediate progression-free survival and OS of patients.[72] Although combination therapy can improve patient survival, TMZ cannot be applied to patients with unmethylated MGMT promoters and has poor efficacy.

TTFields in combination with targeted therapy

Molecularly targeted therapies are rapidly evolving in oncology treatment. The first targeted drug therapy found to be applied to recurrent GBM was bevacizumab, a single-target antagonist targeting vascular endothelial growth factor-A. The aggressiveness, malignancy, and therapeutic efficacy of gliomas are closely related to vascular endothelial growth factor.[77],[78] Several studies have shown significant efficacy on bevacizumab for the treatment of recurrent GBM, with patients having 6-month progression-free survival rates >40%, OS rates >70% beyond 6 months, and objective response rate between 50% and 60%.[79],[80] In a study of 921 patients with newly diagnosed GBM, the better efficacy and safety of bevacizumab application in patients with newly diagnosed GBM was confirmed.[81],[82] Regorafenib, a multiple kinase inhibitor, improved survival time in patients with recurrent GBM.[83] Another MET kinase inhibitor targeting the PRZ1-MET fusion gene-PLB1001-also has good antitumor effects.[84] Darafenib, an inhibitor targeting the BRAF target, a common gene mutation in childhood gliomas, has shown some effectiveness in phase II clinical trials.[85] One study reported a patient with recurrent cystic glioblastoma who did not respond significantly to bevacizumab and instead added TTFields, which slowly reduced the tumor cyst after 6 cycles, with a resolution of cystic enhancement and peritumor cerebral edema.[86] bevacizumab was approved for recurrent glioblastoma in 2009.[87] Bevacizumab directly inhibits vascular endothelial proliferation of tumors and also normalizes tumor vasculature.

There are also clinical studies that applied three drugs, TMZ, bevacizumab, and irinotecan, in combination with TTFields to prolong the median OS and progression-free survival of patients.[88] Another drug, sorafenib, increases the sensitivity of glioma cells to TTFields, and sorafenib combined with TTFields treatment accelerates apoptosis and inhibits the motility and invasiveness of cancer cells and angiogenesis through the production of reactive oxygen species.[89]

TTFields combined immunotherapy

Immunotherapy mainly activates cytotoxic T lymphocytes or increases exogenous cytotoxic T lymphocytes to act directly and kill cancer cells. One phase III clinical study showed that nivolumab did not prolong patient survival in recurrent GBM.[90] Another phase II clinical study using PD-1 monoclonal antibody (neoadjuvant) and postoperative adjuvant use in surgically resectable recurrent GBM showed that neoadjuvant therapy prolonged patients' OS more than postoperative use.[91] Immunological approaches used for glioma include peripatetic immunotherapy, active immunotherapy, and passive immunotherapy. Dendritic cells (DCs) vaccines are relatively widely used in active immunization.[92] DC vaccines include Glioma antigenic peptide sensitized and extract sensitized DC vaccines, Glioma cellular DCs fusion vaccines, Glioma nucleic acid molecule sensitized DC vaccines, and Glioma apoptotic vesicle sensitized DC vaccines.[93] Some studies have shown good results for patients vaccinated with tumor-sensitized DC vaccine after observation.[94] It has also been shown that DC vaccines made after tumor RNA transfection were administered to relapsed GBM and similarly achieved good therapeutic results.[95] Passive immunotherapy is the use of monoclonal antibodies targeting drugs to inhibit relevant immune molecules and pathways to increase the body's level of immunity against tumors.[96] Recently, there are studies including interleukin-2, mucin monoclonal antibodies,[97] anti-CD24 monoclonal antibodies, and soluble CD70 molecules,[98] and other new approaches to lymphocyte perinatal immunization are under investigation.[99] It has been shown that Ag-specific T cells (Ag-specific T cells) in glioblastoma do not change activity and function under adjuvant treatment with TTFields. Tumor characteristics change to anti-tumor immune characteristics after TTFields treatment, with no reduction in T cell infiltration and T cells retaining critical anti-tumor functions.[100] TTFields combination immunotherapy is currently in clinical trials, such as peptide vaccines, immune check inhibitors, and mutation-derived tumor antigen vaccine classes, among others. Glioma is immunosuppressive and immunotherapy has a promising future in the treatment of glioma, and the advent of TTFields provides a new research direction.

TTFields combined with targeted craniectomy

New research has recently combined targeted craniectomy with TTFields for the treatment of gliomas, where the cranial bone may block the entry of magnetic fields into the skull and targeted removal of the cranial bone may enhance the intracranial magnetic field strength. One study took a patient with a left-sided cortical glioblastoma and another with a right-sided deep thalamic mesenchymal astrocytoma, virtually removed the skull above the tumor, and applied MRI data techniques to calculate the electric field distribution in the head, showing that removing the skull increased the electric field strength within the tumor by 60%–70% and that multiple small burr holes were more effective than the same area of skull removal.[46] Cranial remodeling surgery, which involves cranial defect or thinning of the skull, has been proposed to redirect the electric current to the lesion site, thereby enhancing the magnetic field. The safety and feasibility of this concept for cranial remodeling surgeons were verified in a clinical phase I trial.[101]

  Limitations Top

With the rapid development of TTFields, the potential gaps in the process of literature search and aggregation and author bias limit this review.

  Conclusions and Future Directions Top

With the development of science and technology, medical technology has also been greatly advanced and the technologies are becoming more and more mature. The application of TTFields and other treatments are also being studied in-depth and updated, combining the characteristics of different patients and individual differences to create different treatment plans to further extend the progression-free survival and OS of patients and improve the prognosis of patients. More efforts are needed to carry out more in-depth research on the selection of different radiation therapy modalities and the combination of radiation therapy with other treatment methods, so as to take advantage of their respective advantages to continuously improve the prognosis of patients. TTFields is a new tumor treatment method, which provides new options for tumor treatment and new hope for patients. Whether TTFields are treated alone or in combination with other treatments, it brings great efficacy to patients and great social benefits to society. As a new treatment method, TTFields still have many problems to be solved, and more in-depth research or exploration is needed to further improve and enhance TTFields. The application of TTFields technology in the field of neurosurgical tumor treatment and other tumor treatment areas should be popularized.



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