Glioma is the most common intracranial primary malignant tumor, and half of it is glioblastoma (also named IDHwt-GBM). The incidence rate of GBM increases with age, with rates highest in patients aged 75 to 84 years (1). According to the report of Central Brain Tumor Registry of the United States (CBTRUS), GBM has the lowest 1-year survival rate (40.9%) and 5-year survival rate (6.6%) compared with other primary brain tumors (2). A single center retrospective study in China included 1,285 patients with glioma, of which 254 were GBM. The 1- and 5-year survival rates were 61% and 9% respectively, in line with what is observed in other countries (3). Standard of care management for GBM involves maximum safe surgical resection, radiation therapy, temozolomide (TMZ) chemotherapy, and consideration of alternating electrical fields. The degree of surgical resection is the most important factor affecting the effect of radiotherapy and chemotherapy and survival. Despite this prognosis remains poor, however, there are promising treatments actively under investigation (4-6).
Systematic guidance is very important to help clinicians make appropriate treatment decisions. Good clinical practice guidelines can improve the overall quality of diagnosis and treatment. In this review we have included Chinese guidelines on the management of glioma. In addition, we also summarized the current situation regarding the surgical, targeted and immunotherapy therapy and tumor treating fields (TTF) of GBM treatment in China, in order to help clinicians and patients make appropriate treatment based on current evidences. We present the following article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-22-18/rc).
Guidelines for glioma management in China
Clinical practice guidelines play an important role in healthcare. Good clinical guidelines can improve the overall diagnosis and treatment level and limit unnecessary treatments and costs. Europe, America and other countries have successively formulated guidelines for glioma treatment (6,7). China has discussed the formulation of guidelines for glioma diagnosis and treatment since 2005 (8).
We systematically searched PubMed, China National Knowledge Infrastructure (CNKI) and Wanfang databases, with the terms “consensus” or “guideline” or “standard”, and “glioma” or “glioblastoma” or “glial tumor”, and “China”. The retrieval time was from the establishment of the database to 24 January 2022. The detailed search strategy was reported in Table 1. Finally, 19 guidelines (8-26) were included, including 8 subclassified as the guideline (8,10,12-15,17,23), 8 subclassified as the consensus (9,11,16,18-20,22,26) and 3 subclassified as the standard (21,24,25). There is 1 guideline focused on low-grade glioma (15), 1 focused on brainstem glioma (16) and 2 focused on pediatric glioma (24,25). Two guidelines (10,14) reported the contents of the system search, 4 guidelines (9,11,12,20) are updated, and 9 guidelines (10,13,14,16-18,20,22,23) reported the source of funding (Table 2). Up to now, the year with the largest number of published guidelines is 2018, with a total of 4 guidelines (17-20) published (Figure 1). Overall, China’s guidelines and expert consensus still need to be improved in terms of preciseness, applicability and editorial independence.
|Date of search||24 Jan, 2022|
|Databases and other sources searched||PubMed, CNKI and Wan Fang databases|
|Search terms used||Search terms: “consensus” or “guideline” or “standard”, and “glioma” or “glioblastoma” or “glial tumor”, and “China”|
|We have presented detailed search strategy of PubMed database in Table S1|
|Timeframe||From origin until 24 January, 2022|
|Inclusion and exclusion criteria||Clinical practice guideline or consensus study|
|English or Chinese Language|
|All guidelines focusing on diagnosis, treatment and or management of gliomas in China were included|
|If guidelines were duplicated, we would select the one with most recent or complete guideline|
|The abstract of guidelines and unpublished drafts of guidelines were excluded|
|Selection process||Two review authors independently collected the data and checked the relative standardized electronic form|
|Any disagreements were settled by discussion or adjudication by other author|
|Collected data items included the title, organization (institution or working group), publish time, and the topic of the target population of guidelines|
CNKI, China National Knowledge Infrastructure.
|Title||Organization||Year||Topic||Evidence-related||Systematic search||Recommendation||Funding source||Update|
|Guidelines for diagnosis and treatment of single disease of gliomas (2005 discussion draft) (8)||Department of Neurosurgery, Affiliated Hospital of Sun Yat-sen University||2005||Gliomas||No||NR||NR||NR||NR|
|Chinese consensus for diagnosis and treatment in central nervous system malignant gliomas (simplified version) (9)||SNO-China||2009||Malignant gliomas||No||NR||Reported||NR||Updated in 2011|
|Chinese guidelines for diagnosis and treatment in central nervous system malignant gliomas (2012) (10)||CGGWC||2013||Gliomas||Yes||Reported||Reported||Society||NR|
|Expert consensus for the removal of functional brain during awake glioma surgery (11)||CGCG||2013||Gliomas||No||NR||Reported||NR||Updated in 2014|
|Guidelines for the removal of functional brain during awake glioma surgery (2014 version) (12)||CGCG||2014||Gliomas||Yes||NR||Reported||NR||Updated in 2018|
|Guidelines for molecular diagnosis and treatment of glioma in China (13)||CGCG||2014||Gliomas||No||NR||Reported||Government||NR|
|Guidelines for diagnosis and treatment of central nervous system glioma in China (2015) (14)||CGGWC||2016||Gliomas||Yes||Reported||Reported||Society||NR|
|Guidelines for surgical treatment of adult supratentorial low-grade gliomas (15)||CGCG||2016||Low-grade gliomas||Yes||NR||Reported||NR||NR|
|Expert consensus for the comprehensive management of brainstem glioma in China (16)||SNO-China, CGCWC||2017||Brainstem gliomas||No||NR||NR||Government||NR|
|Guidelines for the removal of functional brain during awake glioma surgery (2018 version) (17)||CGCG, GPCCMA||2018||Gliomas||Yes||NR||Reported||Government||NR|
|Expert consensus for the multidisciplinary diagnosis and treatment of glioma in China (18)||SNO-China||2018||Gliomas||No||NR||NR||Society||NR|
|Expert consensus of China on radiation therapy for gliomas in 2017, (19)||China Society for Radiation Oncology||2018||Gliomas||Yes||NR||Reported||NR||NR|
|Expert consensus on immune and targeted therapy of central nervous system gliomas in China (20)||GPCCMA, Neuro-Oncology branch of Shanghai Anti-cancer Association||2018||Gliomas||Yes||NR||Reported||Government||Updated in 2020|
|Guidelines for diagnosis and treatment of glioma (2018 version) (21)||Bureau of Medical Administration of National Health Commission||2019||Gliomas||Yes||NR||Reported||NR||NR|
|Expert consensus on immune and targeted therapy of central nervous system gliomas in China (second edition) (22)||GPCCMA, Neuro-Oncology branch of Shanghai Anti-cancer Association||2020||Gliomas||Yes||NR||Reported||Government||NR|
|Clinical practice guidelines for the management of adult diffuse gliomas (23)||CGCG, SNO-China, CBCA, CGGA, AGGA||2021||Adult diffuse gliomas||Yes||NR||Reported||Government||NR|
|Guidelines for the management of pediatric brain gliomas in China (2021 version) (24)||National Health Commission of the People’s Republic of China||2021||Pediatric gliomas||No||NR||NR||NR||NR|
|Guidelines for the management of pediatric ependymoma in China (2021 version) (25)||National Health Commission of the People’s Republic of China||2021||Ependymoma||No||NR||NR||NR||NR|
|Expert consensus on tumor electric field therapy for glioblastoma in China (26)||Glioma Professional Committee of China Anti-Cancer Association, CGCWC||2021||Glioblastoma||No||NR||Reported||NR||NR|
NR, not reported; SNO-China: Society for Neuro-Oncology of China; CGGWC, Chinese Glioma Guideline Working Committee; CGCG, Chinese Glioma Cooperative Group; CGCWC, Chinese Glioma Consensus Working Committee; GPCCMA, Glioma Professional Committee of Chinese Medical Association; CBCA, Chinese Brain Cancer Association; CGGA, Chinese Glioma Genome Atlas; AGGA, Asian Glioma Genome Atlas.
Surgical treatment is the first choice for patients with GBM. On the premise of fully protecting the patient’s brain function, the tumor tissue can be removed to the greatest extent (27,28). Several assistive technologies, including intraoperative magnetic resonance imaging (MRI) scanning, intraoperative ultrasound, fluorescence contrast and neuro-navigation, can be used to observe and confirm whether there is residual tumor (7,29).
Neuro-navigation integrates the structural and functional image information obtained before operation into neuro-navigation, registers reference points and reference frames, and determines important anatomical structures, so as to shorten the time of intraoperative functional positioning. Neuro-navigation device have been equipped by many large academic hospitals in urban centers, for example Beijing, Shanghai, Guangzhou, Wuhan, and so on.
At present, the main problem of intraoperative neuro-navigation is brain displacement, but intraoperative MRI can correct brain displacement and update navigation in real time, which is helpful to improve the resection degree of glioma (30). In addition, intraoperative ultrasound can guide the operator to judge the lesion location and resection degree in real time through the bone window, which is easy to popularize, but its image is easy to be affected by section, air, edema, etc. (31). Because of the high price and high requirements for surgical instruments, only a few academic hospitals have equipped the intraoperative MRI, such as Beijing Tiantan Hospital, Huashan Hospital in Shanghai and so on.
The surgical technique of resection of gliomas in brain functional areas in wake-up state is regarded as an important technique to safely remove gliomas in brain functional areas to the greatest extent. At present, it is still a hot and difficult issue in the field of surgery. In 2013, China first published the expert consensus on the surgical technology of removing gliomas in brain functional areas in wake-up state (11). Based on the release of new research results, the Chinese brain glioma group updated the guidelines in 2014 (12) and 2018 (17) respectively to further improve the standardization and standards of surgery. At present, the key to resection of gliomas in brain functional areas under wake-up anesthesia lies in the detection and protection of important functional structures. Although Chinese hospitals carried out wake-up surgery in the 1990s, considering the technical requirements of anesthesiologists, the cooperation of patients and the extension of operation time, this technology has not been well promoted at present. Only few neurosurgeons in the academic hospitals, such as Beijing Tiantan Hospital, Huashan Hospital in Shanghai, Zhongnan Hospital of Wuhan university, and so on, regularly performed the wake-up craniotomy for patients with GBM located in brain functional areas.
Although China’s guidelines recommend image technology to assist surgical treatment, it is difficult to completely remove the real tumor boundary due to the diffuse, invasive and special location of GBM. Further research is still needed to overcome this problem.
Targeted therapy and immunotherapy
The standard treatment of GBM includes maximum surgical resection, postoperative radiotherapy and TMZ chemotherapy, but these may have immunosuppressive effect. Coupled with the immune particularity of the central nervous system, GBM is a disease that is difficult to be treated by immune pathway. However, the new study found that the central nervous system has an appropriate immune response and is connected with the peripheral immune system (32). At the same time, GBM growth can destroy the blood-brain barrier and facilitate the entry and exit of lymphocytes into and out of brain tissue (33). These provide a theoretical basis for immunotherapy of GBM. In recent years, targeted therapy represented by bevacizumab (BEV) has been widely used in clinical treatment. New targeted therapy medicine for GBM, such as a MET kinase inhibitor PLB-1001, also demonstrated remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models in China (34). At present, a variety of GBM immunotherapy methods have entered the stage of clinical trials, mainly including immune checkpoint inhibitors, chimeric antigen receptor T (CAR-T) cells and vaccines.
BEV is a human clonal antibody that blocks tumor angiogenesis by inhibiting vascular endothelial growth factor. It can prevent epithelial growth factor receptor (EGFR) from binding to its receptor and reduce tumor cardiovascular formation, so as to inhibit tumor growth. The US Food and Drug Administration (FDA) first approved BEV for the treatment of recurrent GBM in 2009 (35). A systematic review included 5 randomized controlled trials (RCTs) with 834 patients provided clear proof of the beneficial effects of BEV treatment in recurrent GBM patients (36). However, two phase III randomized controlled trial of BEV combined with standard first-line radiotherapy and chemotherapy in the treatment of newly diagnosed GBM showed that BEV could not prolong the overall survival (OS), only could improve the progression free survival (PFS) (37-39). The study of BEV combined with TMZ in the treatment of recurrent GBM in China showed that the effect is better in the short term, but there was no significant difference in the long-term curative effect between China and foreign countries (40). Based on the current evidence, China’s guidelines (22) reported that BEV was not recommended in combination with standard treatment for newly GBM patients, except for the guidance of clear molecular markers and other test results. BEV was recommended for patients with recurrent GBM. In addition, clinical trials on BEV are combination therapy in China. For recurrent GBM, BEV combined with hypofractionated re-radiation, Camrelizumab, ASC40 tablets, Irinotecan plus re-radiotherapy, and Nimustine (ChiCTR2000035881, NCT04952571, NCT05201326, NCT05118776, NCT02698280). Most trials are in the recruitment stage. One ongoing clinical trial to explore the potential image biomarkers in newly GBM with BEV (NCT01939574) (Table 3)
|Title||NCT number||Study type||Institution||Date of registration||Trial phase||Patients (N)||Treatment||Primary outcomes|
|Experimental group||Control group|
|Efficacy and safety of hypofractionated re-radiation therapy plus bevacizumab versus bevacizumab alone in the treatment of recurrent glioblastoma: a prospective, single-center, phase II, parallel, randomized, controlled trial||ChiCTR2000035881||RCT||Fudan University Huashan Hospital||Aug-2020||Phase 2||Recurrent GBM (N=86)||Bevacizumab + HFRT||Bevacizumab||PFS|
|An exploratory study on camrelizumab combined with bevacizumab for adult patients with recurrent GBM||NCT04952571||Interventional study||Beijing Sanbo Brain Hospital||Jul-2021||Phase 2||Recurrent GBM (N=94)||Bevacizumab + Camrelizumab||Bevacizumab||PFS at 6 months|
|A phase III randomized, double-blind, placebo-controlled, multi-center trial to evaluate safety and efficacy pf ASC40 tablets combined with bevacizumab in subjects with recurrent glioblastoma||NCT05118776||RCT||Beijing Tiantan Hospital, Capital Medical University||Nov-2021||Phase 3||Recurrent GBM (N=180)||Bevacizumab + ASC40 tablets||Bevacizumab + placebo||PFS and OS|
|An open-label, single arm study to explore whether potential image biomarkers correlate with efficacy of bevacizumab combined with conventional therapy in newly diagnosed glioblastoma||NCT01939574||Single arm study||Shandong Cancer Hospital and Institute||Aug-2013||NA||Newly diagnosed GBM (N=20)||Bevacizumab + standard treatment||PFS and image biomarker change|
|Phase II study of bevacizumab and Nimustine in patients with recurrent high-grade glioma||NCT02698280||Single arm study||Huashan Hospital, Fudan University||Mar-2016||Phase 2 (completed)||Recurrent GBM (N=23)||Bevacizumab + Nimustine||All cause response within 3 weeks|
|An open and single-arm prospective clinical study of the safety and efficacy of irinotecan and bevacizumab combined with re-radiotherapy in the treatment of recurrent glioblastoma||NCT05201326||Single arm Study||Ruijin Hospital, Shanghai Jiao Tong University School of Medicine||Jan-2022||Phase 1||Recurrent GBM (N=20)||Bevacizumab + Irinotecan + re-radiotherapy||SAE at 28 days|
|B7-H3-targeted CAR-T cells in treating patients with recurrent or refractory glioblastoma||NCT04077866||RCT||Second Affiliated Hospital, School of Medicine, Zhejiang University||Sep-2019||Phase 2||Recurrent and refractory GBM (N=40)||Anti-B7-H3 CAR-T + TMZ||TMZ||OS|
|A safety and efficacy study of autologous chimeric antigen receptor engineered T cells redirected to EGFRvIII in patients with recurrent glioblastoma multiforme||NCT02844062||Single arm study||Beijing Sanbo Brain Hospital||Jul-2016||Phase 1||Recurrent GBM (N=20)||Anti-EGFRvIII CAR-T + Cyclophosphamide + Fludarabine||IAE|
|A safety and efficacy study of autologous chimeric switch receptor engineered T cells redirected to PD-L1 in patients with recurrent glioblastoma multiforme||NCT02937844||Single arm study||Sanbo Brain Hospital, Capital Medical University||Oct-2016||Phase 1||Recurrent GBM (N=20)||Anti-PD-L1 CSR-T + Cyclophosphamide + Fludarabine||NAE|
|A clinical study to investigate the safety, tolerance and efficacy evaluation of single-centre, open-label of local treatment of CD147-CAR-T in recurrent glioblastoma||NCT04045847||Single arm study||National Translational Science Center for Molecular Medicine & Department of Cell Biology||Aug-2019||Early Phase 1||Recurrent GBM (N=31)||CD147-CAR-T||Incidence and type of AE|
|A pilot study of CAR-T cells targeting B7-H3 antigen in treating patients with recurrent and refractory glioblastoma||NCT04385173||Single arm study||Second Affiliated Hospital, School of Medicine, Zhejiang University||May-2020||Phase 1||Recurrent and refractory GBM (N=12)||Anti-B7-H3 CAR-T + TMZ||AE; MTD; OS and PFS|
|An open, single-arm, phase 1 study to evaluate the safety/preliminary effectiveness and determine the maximal tolerated dose of B7-H3-targeting CAR-T cell therapy in treating recurrent glioblastomas||NCT05241392||Single arm study||Beijing Tiantan Hospital||Feb-2022||Phase 1||Recurrent GBM (N=30)||Anti-B7-H3 CAR-T||DLT; Incidence and severity of AE|
|A triple-blind randomized clinical study of vaccination with dendritic cells loaded with glioma stem-like cells associated antigens against brain glioblastoma multiform||NCT01567202||RCT||Huashan Hospital, Fudan University||Mar-2012||Phase 2||GBM (N=100)||DC vaccination + standard treatment||Blank placebo + standard treatment||ORR|
|Clinical study of a dendritic cell vaccine combined with immune checkpoint inhibitors for treatment of glioblastoma||ChiCTR1900025835||Observational study||Chinese People’s Liberation Army General Hospital||Sep-2019||Phase 0||GBM (N=30)||DC vaccine + standard treatment||Standard treatment||MRI results; PFS; OS; Quality of life score|
|DC vaccine + standard treatment + immune checkpoint blocker|
|Neoadjuvant PD-1 antibody alone or combined with autologous glioblastoma stem-like cell antigens-primed DC vaccines (GSC-DCV) for patients with recurrent glioblastoma: A phase II, randomized controlled, double blind clinical trial||NCT04888611||RCT||Huashan Hospital, Fudan University||May-2021||Phase 2||Recurrent GBM (N=40)||DC vaccine + Camrelizumab||Placebo + Camrelizumab||OS and PFS|
|Personalized cellular vaccine therapy in treating patients with newly diagnosed glioblastoma (PerCellVac)||NCT02709616||Single arm study||Guangdong 999 Brain Hospital||Mar-2016||Phase 1||Newly diagnosed GBM (N=10)||Personalized DC-based vaccine + standard treatment||Incidence of AE and SAE|
|Personalized cellular vaccine therapy in treating patients with recurrent glioblastoma (PerCellVac2)||NCT02808364||Single arm study||Guangdong 999 Brain Hospital||Jun-2016||Phase 1||Recurrent GBM (N=10)||Autologous DC||Incidence of AE and SAE|
|Clinical study of a dendritic and glioma cells fusion vaccine with IL-12 for treatment-naïve GBM patients||NCT04388033||Single arm study||Second Affiliated Hospital, School of Medicine, Zhejiang University||May-2020||Phase 2||Treatment-naïve GBM (N=10)||DC vaccine + IL-12 + standard treatment||AE; SAE; PFS at 6 months|
|Phase I clinical study of safety & efficacy of DC vaccine and TMZ for the treatment of newly-diagnosed glioblastoma after surgery||NCT04968366||Single arm study||Beijing Tiantan Hospital||Jul-2021||Phase 1||Newly diagnosed GBM (N=10)||DC vaccine + TMZ||IAE|
|To evaluate the safety and efficacy of wearable glioma electric field therapy combined with temozolomide in the treatment of recurrent GBM: a randomized, controlled, open-label, multicenter trial||ChiCTR2000034285||RCT||Beijing Tiantan Hospital, Capital Medical University||Jun-2020||Phase 0||Recurrent GBM (N=300)||TTF + TMZ||TMZ||OS|
|Prospective, multicenter, open, randomized, parallel controlled trial for tumor treating fields (EFE-G100) combined with temozolomide versus temozolomide alone in patients with newly diagnosed glioblastoma||ChiCTR2000034706||RCT||Huashan Hospital Affiliated to Fudan University||Jul-2020||NA||Newly diagnosed GBM (N=330)||TTF + TMZ||TMZ||PFS|
|The clinical effect and safety of radiotherapy Concurrent of TTF in the treatment of post-operation patients with glioblastoma||NCT04902586||RCT||Zhongnan Hospital, Wuhan||May-2021||NA||GBM (N=30)||TTF + radiotherapy + TMZ||Radiotherapy +TMZ||Disease-free survival time|
|Evaluate the efficacy and safety of tumor electric field therapy system in the treatment of newly diagnosed supratentorial glioblastoma||ChiCTR2100047049||Interventional study||Beijing Tiantan Hospital, Capital Medical University||Jun-2021||NA||Newly diagnosed supratentorial GBM (N=411)||TTF + TMZ||TMZ||PFS|
|A prospective, single-center, single-arm, exploratory study on the treatment of recurrent glioblastoma with Tumor Electric Fields Treatment System||ChiCTR2000032655||Single arm study||Xiangya Hospital Central South University||May-2020||Phase 0||Recurrent GBM (N=5)||TTF||Frequency of AE and SAE|
|A prospective, single-center, single-arm, exploratory study on the treatment of recurrent glioblastoma with Tumor Electric Fields Treatment System||NCT04417933||Single arm study||Xiangya Hospital of Central South University||Jun-2020||Early Phase 1||Recurrent GBM (N=5)||TTF||AE; time to Progression; OS at 12 months|
|A prospective, open-label, single-arm clinical Study evaluating TTF in combination with chemotherapy for recurrent glioblastoma||NCT04689087||Single arm study||Sun Yat-sen University Cancer Center||Dec-2020||NA||Recurrent GBM (N=40)||TTF + second-line chemotherapy||OS at 6 months|
|A single-arm, open, single-center exploratory clinical study of the safety and efficacy of concurrent postoperative radiotherapy and adjuvant temozolomide combined with tumor treating fields/apatinib in patients newly diagnosed with glioblastoma||ChiCTR2100041969||Single arm study||West China Hospital||Jan-2021||Phase 2||Newly diagnosed GBM (N=30)||TTF||PFS at 12 months|
Standard treatment: including surgery, TMZ-chemotherapy and radiotherapy. AE, adverse events; CAR-T, chimeric antigen receptor T; CSR-T, chimeric switch receptor T; DC, dendritic cells; DLT, incidence of dose limiting toxicity; EGFRvIII, epithelial growth factor receptor variant type III; GBM, glioblastoma; HFRT, hypofractionated re-radiation therapy; IAE, incident of adverse events; IL-12, interleukin 12; MRI, magnetic resonance imaging; MTD, maximum tolerated dose; NA, not applicable; NAE, number of adverse events; NCT, National Clinical Trial; ORR, objective response rate; OS, overall survival; PD-L1, programmed cell death 1 ligand 1; PFS, progression-free survival; RCT, randomized controlled trial; SAE, serious adverse events; TMZ, temozolomide; TTF, tumor treating fields.
CAR-T cell therapy
CAR-T cell therapy, namely chimeric antigen receptor T cell therapy. By using the patient’s own T lymphocytes, they are remodeled in the laboratory, loaded with receptors and costimulatory molecules that recognize tumor antigens, amplified in vitro and then reinfused into the patient’s body, so as to identify and attack their own tumor cells. CAR-T therapy solves the problem of tumor heterogeneity. The transformed T cells can target tumor cells, but the toxic reactions of treatment need to be closely monitored and treated. The common targets of CAR-T therapy in GBM are EGFR variant type III (EGFRvIII), human epithelial growth factor receptor 2 (HER2) and interleukin 13 receptor alpha 2 (IL-13R α 2), etc. (41). In addition, there are some promising antigens characterized by high expression of GBM, such as B7-H3 and CSPG4 (42,43). The first CAR-T clinical trial directed to EGFRvIII in 10 recurrent GBM patients showed that the median OS time was 8 months, and the clinical benefit was not significant (44). Another CAR-T clinical trial with HER2 as the target indicated that the median OS after the first infusion of T-cell and diagnosis in 17 patients with progressive GBM were 11.1 and 24.5 months respectively, and 8 patients had clinical benefits (45). Besides, there are also some encouraging results in the research of CAR-T in the treatment of GBM, but further research is needed to achieve stable clinical benefits (46,47). Treatment of GBM with CAR-T is plagued by the lack of ideal tumor antigens as targets and serious side effects. There are six ongoing clinical trials of CAR-T therapy for recurrent GBM in China (NCT04385173, NCT02844062, NCT04045847, NCT04077866, NCT05241392, NCT02937844), of which 3 trials were treated with anti-B7-H3 CAR-T and 1 was treated with CD147 CAR-T (Table 3).
Dendritic cells (DC) vaccine
DC are derived from bone marrow hematopoietic progenitor cells or monocytes. They are the most powerful antigen-presenting cells known at present. They can activate the body’s specific immunity by efficiently ingesting, processing and presenting antigens to T and B lymphocytes. DC vaccine is to use DC to present antigen and activate immunity. DC that can specifically recognize tumors induced or constructed in vitro, can be imported back into tumor patients to activate the immune response of T cells to tumors. A multicenter phase III clinical trial showed that the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard treatment may improve the median survival of GBM (48). One phase II clinical trial in China reported that DC vaccine may significantly prolong the OS of GBM patients. GBM patients with IDH1 wild-type, TERT mutation and low expression of B7-H4 are more sensitive to specific active immunotherapy activated by Glioblastoma stem-like cell antigens-primed DC vaccines (GSC-DCV) (49). Based on the current research, China’s latest guidelines recommend that DC vaccine can be used in the relevant clinical trials of recurrent GBM. In recent years, the “personalized DC vaccine” was proposed according to tumor heterogeneity, which can provide more accurate treatment for different tumor patients. At present, there are two ongoing clinical trials (NCT02709616, NCT02808364) on personalized DC vaccine for the treatment of newly GBM and recurrent GBM in China, and five studies on DC vaccine combined with TMZ, programmed cell death 1 (PD-1) and interleukin 12 (IL-12) for the treatment of GBM (ChiCTR1900025835, NCT01567202, NCT04968366, NCT04888611, NCT04388033) (Table 3).
Tumor treating fields
TTF is a new type of physical therapy. It interferes with the mitosis of tumor cells by acting on the tubulin of proliferating cancer cells, causes the apoptosis of affected cancer cells and inhibits tumor growth. The Food and Drug Administration approved TTF product Optune® to treat adult patients with recurrent and newly diagnosed GBM in 2011 and 2015 respectively, based on the positive clinical trial results (4,50,51). In 2015, TTF technology was incorporated into the guidelines for the diagnosis and treatment of glioma of the nervous system in China (14). In 2018, the National Health Commission of China published the standard for the diagnosis and treatment of glioma (2018 version) (21), and TTF was recommended for the treatment of new GBM (level I evidence) and recurrent high-grade glioma (Level II evidence). In May 2020, China’s Drug Administration approved the combination of TTF and TMZ for the treatment of newly diagnosed GBM patients and as a monotherapy for recurrent GBM patients. In 2021, experts such as the glioma Professional Committee of China Anti-Cancer Association prepared an expert consensus on electric field treatment of GBM, and made a detailed report on the action mechanism, influencing factors, clinical evaluation, use scheme and patient management of TTF in the treatment of GBM (26). However, the application research of TTF in China is limited. At present, clinical trials are promoting the combination of TTF with radiotherapy and chemotherapy, targeted therapy, immunotherapy and so on. In addition, six ongoing clinical trials in China are trying to determine the safety and efficacy of TTF combined with radiotherapy and chemotherapy (ChiCTR2100047049, ChiCTR2100041969, ChiCTR2000034706, ChiCTR2000034285, NCT04689087, NCT04902586). Two ongoing clinical trials in China explore the recurrent GBM with TTF treatment system (ChiCTR2000032655, NCT04417933) (Table 3).
In summary, glioma guidelines in China are increasing year by year, and the quality of guidelines is also gradually improving, but the preciseness, applicability and independence of guidelines still need to be further improved. At present, emerging immune and targeted therapy are under research in China. However, the cooperation in clinical research of GBM in multiple centers needs to be strengthened in China.
We express our gratitude to Xian-Tao Zeng from Zhongnan Hospital of Wuhan University for his support and help in database system search.
Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-22-18/rc
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (https://cco.amegroups.com/article/view/10.21037/cco-22-18/coif).The authors have no conflicts of interest to declare.
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