Inventory 2021
There is no end to life, only continuous progress
The extraordinary 2021 is far away from us
The new year is also a new rush
I believe that 2022 will be a wonderful year
Inventory is the best goodbye
【Medical Delight Hui】Maintain tradition
We sincerely invite big names in the field of oncology
Continue to launch the New Year's Special Edition [Annual Inventory]
Summarize the progress of oncology disciplines in 2021
Words as a medium, words as a mirror
Bringing together and deciphering 2021 belongs to oncologists
Issue 14
Dr. Chen Zhongping, Center for Cancer Prevention and Treatment, Sun Yat-sen University, Dr. Depei Li
Clinical research progress of glioma in 2021
Invited experts
Professor Chen Zhongping
Chief physician, professor, doctoral supervisor
Director of the Department of Neurologic Science and Technology Innovation, Cancer Prevention and Treatment Center of Sun Yat-sen University
Chief specialist in glioma monopathy
China's Top 100 Famous Doctors "Top 10 Doctors for Glioma Surgery"
Founder of the Neuro-Oncology Professional Committee of the Chinese Anti-Cancer Association
Guangdong Province/Guangzhou Anti-Cancer Association Neuro-Tumor Professional Committee
Dr. Depei Li
Department of Neurosurgery, Cancer Prevention and Control Center, Sun Yat-sen University
As the first author, he has published more than ten papers in academic journals such as J Neuro-Oncol, Glioma and Front Cell Dev Biol, and his research results have been selected for international academic conferences such as the American/European Annual Conference on Neuro-Oncology (SNO/EANO), and have won 1 national utility model patent.
Inventory 2021
Clinical research progress of glioma
Gliomas are the most common primary malignancies of the central nervous system (CNS), more than half of which are highly malignant glioblastomas, with poor prognosis and many challenges to treatment. Clinical and scientific researchers explore from the aspects of experimental research, targeted immunotherapy and combination therapy, and this article will introduce the relevant important research in the field of glioma diagnosis and treatment in 2021 for the benefit of readers.
1 Progress in glioma pathology
The Classification of Central Nervous System Tumors of the World Health Organization (WHO) is an important basis for the clinical diagnosis and treatment of neuroneoplasms, and after more than 40 years of development, it has gradually been updated from a histology-based classification system to a new classification of WHO CNS5 in 2021 [1], proposing to jointly define tumor types by histology, biology and molecular characteristics, highlighting the role of molecular pathology.
Major changes in WHO CNS5 include 1) separating paediatric diffuse gliomas due to large differences in molecular properties and clinical outcomes in adult and pediatric gliomas. However, the pediatric type may occur in adults, such as IDH wild-type astrocytomas that occur in young people, so be wary of the possibility of pediatric gliomas. 2) The classification of adult-type diffuse gliomas is simplified, and only 3 categories are proposed [i.e., glioblastoma (GBM), IDH wild type; astrocytoma, IDH mutant type and oligodendrocyte glioma, IDH mutant type with 1p/19q joint deletion]. 3) Pediatric diffuse gliomas are divided into low-grade and high-grade gliomas, which require the integration of molecular features for comprehensive diagnosis, and the term glioblastoma is no longer used in children. High-grade gliomas in children include: Diffuse midline glioma, H3 K27 variant; Diffuse hemispheric glioma, H3G34 mutant; Diffuse high-grade gliomas, H3 wild and IDH wild type; And 4 types of infantile hemisphere gliomas. Low-grade diffuse gliomas in children include four types: MAPK pathway variant, MYB/MYBL1 variant, vascular center, and juvenile polymorphic low-grade neuroepithelial tumors. In addition, localized growth astrocytomas such as hair cell astrocytomas and polymorphic xanthoma astrocytomas often have changes in MAPK pathway genes, including NF1 mutations, BRAF mutations or fusions, FGFR1 mutations or fusions. 4) In view of the fact that different types of neural tumors can be very different even if the WHO classification is the same, the biological behavior and clinical process can be very different, the new version of the classification adopts the tumor type classification, reflecting the biological similarity and natural course of the tumor type, and the classification of different types of CNS tumors does not require a unified standard. In addition, tumor grading should also consider molecular characteristics, such as IDH mutant astrocytomas with CNKN2A/B purification deletion can be determined as WHO4 grade.
2 Advances in antineoplastic therapy
At present, the first-line treatment regimen for malignant glioma is still mainly temozolomide (TMZ) chemotherapy, and the progress of targeted therapy with precision and effectiveness is slow. Chemotherapy for anaplastic astrocyte tumor (WHO grade 3) often refers to GBM to administer a synchronized and adjuvant TMZ regimen in China, but a large multicenter phase III CATNON study found that adjuvant therapy with TMZ significantly improved patient survival, but there was no greater survival benefit from radiotherapy synchronized with TMZ [2], a result that is closely related to clinical decision-making. DB102 is the world's first small molecule serine/threonine kinase inhibitor, which acts on key tumor targets such as PI3K/AKT, exerting direct anti-tumor and inhibiting neovascularization. Patients with positive DGM1 expression have been found to be sensitive to DB102 treatment in studies of diffuse large B-cell lymphoma, and DB102 has also been observed in retrospective analysis to significantly improve survival in DGM1-positive GBM patients [3]. As a result, it has gained widespread attention and entered the fast-track approval channel of the US FDA, and is currently undergoing a global Phase III trial. Common MAPK pathway genetic alterations in pediatric gliomas, a multicenter Phase II clinical trial evaluating trametinib in progression of MAPK/ERK pathway activation or refractory childhood and youth gliomas ( <25 years of age), a total of 150 patients with NF1 mutations, BRAF fusion, and other types of MAPK pathway genetic alterations were planned, and interim results showed an objective response rate of 50 percent and usually rapid response [4]. In another ROAR study of tremetinib combined with Dabrafenib (a BRAF inhibitor) for adult recurrent gliomas with BRAFV600E mutations, combination therapy demonstrated meaningful clinical benefits, with an objective response rate of 33 percent in 45 patients with high-grade gliomas enrolled and a 69 percent response rate in 13 low-grade gliomas [5]. Diffuse midline gliomas with H3 K27M mutations are more likely to occur in children and adolescents, and there is a lack of effective treatment and a very poor prognosis. ONC201 is the first orally targeted agent for H3 K27M mutations, and a clinical trial of ONC201 monotherapy with recurrent diffuse midline glioma with H3 K27M mutations involved 50 patients with an objective response rate of 30 percent and a median survival of 13.7 months, providing a glimmer of hope for these refractory diseases [6].
The Tumor Treatment Electric Field (TTF) is a new weapon in glioma treatment that is becoming increasingly familiar. According to the results of the EF-14 trial, the routine use of TTF is the adjuvant chemotherapy stage after surgery and radiotherapy, but whether the use of TTF in advance in the radiotherapy phase can further improve the efficacy is a widely interested direction, and there are currently multiple clinical trials actively exploring this problem, including trials such as PriCoTTF and TRIDENT. TTF therapeutic resistance is also a research hotspot, and experimental studies have found that glioma cell sensitivity decreases after TTF treatment and upregulates the PI3K/AKT/mTOR signaling channel, while the combination of TTF and PI3K inhibitors can reverse the therapeutic resistance of glioma to TTF [7]. Based on the safe and effective results suggested by clinical phase I exploration, a phase II clinical trial of "OptimalTTF-2" drilling five 1.5 cm diameter bone holes on the surface of the tumor is trying to recur gliomas [8], and a new breakthrough is expected.
3 Progress in immunotherapy
The high heterogeneity of gliomas and therapeutic resistance are important reasons for the difficulty in the development of new cytotoxic drugs and targeted drugs, and immunotherapy mobilizing the immune system to attack tumor cells through adoptive immune cells or modulating the microenvironment may be another promising direction to overcome gliomas. The breakthrough of PD-1 monoclonal antibody in solid tumors such as lung cancer and liver cancer is obvious to all, but from the results of several phase III clinical trials that have been completed (CheckMate-143, CheckMate-498, CheckMate-548), it seems that PD-1 monoclonal antibody monoclonal antibody or combination bevacizumab can not effectively improve the survival of patients with newly diagnosed or recurrent glioblastoma. The effect of PD-L1 monoclonal antibody was also unsatisfactory, and the results of a one-arm Phase I/II clinical trial conducted by Weathers et al. [9] found no significant improvement in the effectiveness of the standard regimen combined with atezolizumab in the treatment of newly diagnosed GBM compared with historical data. The reason for the failure of PD-1/PD-L1 treatment is related to the low infiltration of glioma T cells and the complex immunosuppressive environment. Macrophages are an important factor in the formation of the glioma-suppressing immune microenvironment, VT1021 targets CD36 and CD47 receptors on the surface of macrophages and blocks the "don't eat me" signal, activating M1 macrophages and cytotoxic T cells. A Phase I/II clinical trial of 32 patients with recurrent GBM showed a better outcome of 50 percent overall disease control rate for VT1021 and better outcomes in patients with CD36/CD47 double high expression [10]. Oncolytic viruses are genetically engineered viruses with self-replication and tumor killing ability, which can not only specifically infect and destroy tumor cells, but also stimulate and synergistically enhance the anti-tumor immune effect. CAN-3110 is a novel HSV oncolytic virus expressing ICP-34.5, with significantly improved replication capacity than the commonly used ICP-34.5 deletion virus, and persistent HSV antigen and inflammatory infiltrates can be observed after treatment of recurrent high-grade gliomas in a Phase I clinical trial, and the median survival of subjects is 11.7 months [11]. Clinical trials of oncolytic virus (DNX-2401 or PVSRIPO) in combination with PD-1 monoclonal antibody for recurrent GBM are also underway, with Phase II trial results showing a median OS of approximately 12 months [12,13], encouraging results, and entering the global Phase III clinical trial phase. In addition, it has been reported that topical treatment (including stereotactic radiosurgery SRS, electric field therapy TTF, laser hyperthermia LITT, etc.) can modulate local inflammation and enhance the effect of immunotherapy, and there are currently several related trials exploring the combination of topical therapy and immunotherapy such as PD-1 monoclonal antibody [14, 15].
4 Summary
The development of molecular pathology is an important progress in the field of glioma in recent years, which has deepened the understanding of the occurrence of glioma in the academic community and laid the foundation for the development of accurate and effective treatment. However, the treatment of glioma is still full of challenges, and how to overcome the heterogeneity and immunosuppressive state of the tumor, find safe and effective targets and markers, and optimize the design of clinical trials needs to be explored. Looking forward to an early breakthrough in glioma treatment!
bibliography
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