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High-grade glioma in children progresses rapidly, and the median survival time of children with recurrence is no more than 6 months.
What is particularly frustrating is that the survival rate of children with high-grade glioma has not improved in the past 30 years.
Yesterday was the first day of the 2021 American Association for Cancer Research (AACR) annual meeting.
It was chosen to announce the results of the Phase 1 clinical trial of HSV-1-based oncolytic virus for the treatment of high-grade glioma in children, and the results were published online at the same time in New England Medicine Magazine (NEJM) also highlights the significance of the experiment.
NEJM Frontiers of Medicine invited Professor Zhang Liwei from the Department of Neurosurgery of Beijing Tiantan Hospital to comment on this important study.
Zhang Yang, Zhang Liwei* Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University; National Neurological Diseases Clinical Research Center* Corresponding author In recent years, the incidence of central nervous system tumors in children has been increasing year by year.
According to reports, central nervous system malignant tumors have become the second most common childhood malignant tumor in my country after leukemia.
In the United States, the incidence of central nervous system tumors in children aged 0-14 has long surpassed leukemia and is the first common childhood tumor.
Gliomas account for 51.
6% of children’s central nervous system tumors (CBTRUS report in 2020), and are mostly malignant; among them, high-grade gliomas (WHO grades Ⅲ-Ⅳ) respond poorly to conventional treatments including surgery, radiotherapy, and chemotherapy.
Early recurrence after recurrence, the median survival time after recurrence is only 5.
6 months.
Limited by the special group of children and the overall lag in the development of new treatments for brain malignant tumors, the therapeutic effect of children with high-grade gliomas has not been substantially improved in the past 30 years.
Therefore, there is an urgent need to discover new treatment methods in order to improve the prognosis of treatment.
Oncolytic viruses have attracted much attention in the field of glioma immunotherapy in recent years.
They can stimulate anti-tumor immune responses and improve tumor immunity by dissolving tumors to release antigens, activating natural immune signaling pathways, and stimulating tumor antigen-presenting cells.
The microenvironment ultimately achieves the immune killing effect of tumors.
In 2018, the New England Journal of Medicine (NEJM) published a Phase 2 clinical trial of adult relapsed glioblastic virus treatment conducted by Duke University using modified poliovirus (PVSRIPO).
The results showed that 21% The patients survived more than 24 months after treatment, and the phenomenon of survival platform appeared, suggesting that these patients may survive for a long time.
This study demonstrates the promising application prospects of oncolytic virus therapy in adult malignant gliomas.
This study is an attempt of oncolytic virus therapy in children with high-grade glioma.
The research was mainly done at the University of Alabama at Birmingham.
The oncolytic virus used is derived from herpes simplex virus type 1 (HSV-1), which is naturally neurotropic and therefore suitable for the treatment of glioma.
Researchers have improved the safety of treatment by genetically modifying the virus to remove its neurotoxicity and ability to replicate in normal cells.
This study is a "3+3" phase 1 clinical trial design.
The main purpose of the study is to conduct 4 intratumoral administration regimens (107 PFU, 108 PFU, 107 PFU+5 Gy radiotherapy, 108 PFU+5 Gy radiotherapy) Safety assessment; the secondary research purpose is the preliminary clinical effect and biological response of the treatment.
A total of 12 cases of recurrent supratentorial high-grade gliomas (10 cases of glioblastoma, 1 case of anaplastic astrocytoma and 1 case of high-grade glioma) were enrolled in the study, all of which were IDH wild-type and refractory cases ( At least two treatments failed).
The results show that the treatment has high safety, treatment-related adverse reactions are mild, and no treatment-related grade 3 to 4 adverse reactions or signs of virus replication in the body are found; the median survival time of patients after receiving treatment is 12.
2 months, which is obvious It is 5.
6 months longer than the historical control group, suggesting that the treatment may have a good therapeutic effect.
Four patients with overall survival of G207 treatment underwent biopsy after treatment.
The study used immunohistochemistry to compare the changes of infiltrating lymphocytes in tumor tissues before and after treatment, and found that there was obvious T lymphocyte infiltration in the tumor after treatment, suggesting that the treatment has the effect of improving the "cold" immune microenvironment of glioma.
However, the above conclusions are relatively preliminary, and it is necessary to use methods such as flow cytometry, single-cell sequencing, transcriptome analysis, and T cell receptor sequencing in future studies to further analyze the types and functions of infiltrating immune cells.
This study also explored the imaging changes related to oncolytic virus therapy.
The results are similar to the results of the Duke University study, indicating that "multivesicular changes" are often the early imaging manifestations of effective treatment.
Similar to other immunotherapies for glioma, the problem of pseudo-progression has also greatly plagued the evaluation of the effect of oncolytic virus therapy.
The current imaging evaluation standard (iRANO) also urgently needs to introduce new imaging methods or methods to further improve the accuracy of imaging evaluation.
The imaging manifestations of patient 002 treated with G207 (modified HSV-1).
Previous studies have shown that the pre-existing protective antibodies against the virus in the body are an important factor in reducing the therapeutic effect of oncolytic viruses.
This study also found similar Phenomenon: The survival time of the 3 patients with pre-existing anti-HSV-1 antibodies was only 5.
1 months, which was much lower than the overall median survival time.
The seropositivity rate of anti-HSV-1 antibodies is as high as 70% to 90% in adults, but fortunately, it is mostly negative in children.
This also suggests that the suitable population for HSV-1 oncolytic virus treatment may be in children.
In summary, this study shows the encouraging results of HSV-1 oncolytic virus treatment in children with malignant gliomas.
Oncolytic virus treatment of childhood gliomas has high safety, and we look forward to the future phase 2-3 clinical trials.
The test further clarified its true therapeutic effect.
Studies also suggest that oncolytic viruses can effectively improve the immune microenvironment of gliomas, thereby providing new strategies for subsequent combination with other immunotherapies such as anti-PD-1/CTLA-4.
In addition, the enrolled cases in this study are all cases of supratentorial glioma.
Children’s brainstem glioma, especially diffuse endogenous pontine glioma (DIPG), is highly malignant and lacks effective treatment methods.
It is also hoped that it will be expanded in the future.
Clinical trials can also fully include this part of patients. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade GliomasFriedman GK, Johnston JM, Bag AK, et al.
DOI: 10.
1056/NEJMoa2024947 Abstract background recurrence in children and adolescents The outcome of patients with sexual or progressive high-grade glioma is poor, with a previous median overall survival of 5.
6 months.
High-grade gliomas in children are basically immune silent or "cold" tumors, with very few tumor infiltrating lymphocytes.
In preclinical studies, children’s brain tumors are highly sensitive to the following oncolytic virus therapies: herpes simplex virus type 1 (HSV-1) G207 that has been genetically engineered to lack genes necessary for replication in normal brain tissue.
Methods We conducted a phase 1 trial of G207 using the 3+3 design.
The trial included children and adolescents who were diagnosed with recurrent or progressive supratentorial brain tumors by biopsy, and divided them into 4 dose cohorts.
Use stereotactic technology to place up to 4 intratumoral catheters for the patient.
The patient received G207 (107 or 108 plaque forming units) administration on the second day.
During the administration, the input rate was controlled so that the administration time lasted for 6 hours.
Patients in cohorts 3 and 4 received gross tumor target radiotherapy (5 Gy) within 24 hours after G207 administration.
This test uses culture and polymerase chain reaction to evaluate the virus excretion through saliva, conjunctiva and blood.
The tumor-infiltrating lymphocytes of the corresponding tissue samples before and after treatment were examined by immunohistochemical methods.
Results Twelve patients with high-grade glioma aged 7-18 years received G207 treatment.
No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigator.
There are 20 grade 1 adverse events that may be related to G207.
No virus excretion was detected.
In this trial, 11 patients were observed to achieve imaging, neuropathology, or clinical remission.
The median overall survival was 12.
2 months (95% confidence interval, 8.
0~16.
4); as of June 5, 2020, 18 months after G207 treatment, 4 out of 11 patients were still alive.
G207 significantly increased the number of tumor infiltrating lymphocytes.
Conclusion After patients with recurrent or progressive high-grade glioma in children received intratumoral administration of G207 and combined radiotherapy with G207, the adverse events were acceptable, and there is evidence that the patient achieved remission.
G207 transforms immune "cold" tumors into "hot" tumors.
(Funded by the US Food and Drug Administration, etc.
; registered in ClinicalTrials.
gov as NCT02457845.
) The author introduces Zhang Liwei, chief physician, second-level professor, doctoral supervisor, and expert enjoying special allowances from the State Council.
He is currently the deputy dean of Beijing Tiantan Hospital and the deputy director of the National Neurological Diseases Clinical Research Center.
He is the president of the Neurosurgery Branch of the Chinese Medical Doctor Association, the executive member of the World Society of Skull Base Surgery (WFSBS), and the executive member of the World Society of Neurosurgery (WFNS) Skull Base Surgery Committee.
He is the editor-in-chief of "NEUROSURGERY" magazine Chinese edition oncology section, deputy editor-in-chief of "Chinese Journal of Neurosurgery" and editorial board member of several publications.
He has made important contributions to the basic research and clinical work of neurosurgery complex diseases of brain stem and skull base tumors.
He has published more than 200 papers and 9 monographs in Nature Genetics, Acta Neuropathologica, Nature Communications, British Medical Journal and other journals.
Won 8 science and technology awards including the National Science and Technology Progress Award.
Cultivate more than 40 master and doctoral students.
Zhang Yang, Deputy Chief Physician of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.
Graduated from the 11-year clinical medicine program of Peking Union Medical College in 2011, completed the doctoral research training in clinical proteomics and tumor immune microenvironment, and obtained MD and PhD degrees.
In the same year, he entered the Department of Neurosurgery of Beijing Tiantan Hospital to engage in clinical work.
His main research areas are the development of new diagnosis and treatment technologies for glioma and immunotherapy.
From June 2018 to June 2019, he completed the clinical translational study of T cell immunotherapy for glioma in the Department of Immunology of Duke University in the United States.
Presided over and participated in 8 national, provincial and ministerial-level projects, and is currently participating in 3 clinical trials of glioma immunotherapy.
He has published more than 10 first author SCI articles and participated in the editing of 3 monographs.
Copyright information This article was translated, written or commissioned by the "NEJM Frontiers of Medicine" jointly created by the Jiahui Medical Research and Education Group (J-Med) and the "New England Journal of Medicine" (NEJM).
The Chinese translation of the full text and the included diagrams are exclusively authorized by the NEJM Group.
If you need to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn.
Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal liabilities.
What is particularly frustrating is that the survival rate of children with high-grade glioma has not improved in the past 30 years.
Yesterday was the first day of the 2021 American Association for Cancer Research (AACR) annual meeting.
It was chosen to announce the results of the Phase 1 clinical trial of HSV-1-based oncolytic virus for the treatment of high-grade glioma in children, and the results were published online at the same time in New England Medicine Magazine (NEJM) also highlights the significance of the experiment.
NEJM Frontiers of Medicine invited Professor Zhang Liwei from the Department of Neurosurgery of Beijing Tiantan Hospital to comment on this important study.
Zhang Yang, Zhang Liwei* Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University; National Neurological Diseases Clinical Research Center* Corresponding author In recent years, the incidence of central nervous system tumors in children has been increasing year by year.
According to reports, central nervous system malignant tumors have become the second most common childhood malignant tumor in my country after leukemia.
In the United States, the incidence of central nervous system tumors in children aged 0-14 has long surpassed leukemia and is the first common childhood tumor.
Gliomas account for 51.
6% of children’s central nervous system tumors (CBTRUS report in 2020), and are mostly malignant; among them, high-grade gliomas (WHO grades Ⅲ-Ⅳ) respond poorly to conventional treatments including surgery, radiotherapy, and chemotherapy.
Early recurrence after recurrence, the median survival time after recurrence is only 5.
6 months.
Limited by the special group of children and the overall lag in the development of new treatments for brain malignant tumors, the therapeutic effect of children with high-grade gliomas has not been substantially improved in the past 30 years.
Therefore, there is an urgent need to discover new treatment methods in order to improve the prognosis of treatment.
Oncolytic viruses have attracted much attention in the field of glioma immunotherapy in recent years.
They can stimulate anti-tumor immune responses and improve tumor immunity by dissolving tumors to release antigens, activating natural immune signaling pathways, and stimulating tumor antigen-presenting cells.
The microenvironment ultimately achieves the immune killing effect of tumors.
In 2018, the New England Journal of Medicine (NEJM) published a Phase 2 clinical trial of adult relapsed glioblastic virus treatment conducted by Duke University using modified poliovirus (PVSRIPO).
The results showed that 21% The patients survived more than 24 months after treatment, and the phenomenon of survival platform appeared, suggesting that these patients may survive for a long time.
This study demonstrates the promising application prospects of oncolytic virus therapy in adult malignant gliomas.
This study is an attempt of oncolytic virus therapy in children with high-grade glioma.
The research was mainly done at the University of Alabama at Birmingham.
The oncolytic virus used is derived from herpes simplex virus type 1 (HSV-1), which is naturally neurotropic and therefore suitable for the treatment of glioma.
Researchers have improved the safety of treatment by genetically modifying the virus to remove its neurotoxicity and ability to replicate in normal cells.
This study is a "3+3" phase 1 clinical trial design.
The main purpose of the study is to conduct 4 intratumoral administration regimens (107 PFU, 108 PFU, 107 PFU+5 Gy radiotherapy, 108 PFU+5 Gy radiotherapy) Safety assessment; the secondary research purpose is the preliminary clinical effect and biological response of the treatment.
A total of 12 cases of recurrent supratentorial high-grade gliomas (10 cases of glioblastoma, 1 case of anaplastic astrocytoma and 1 case of high-grade glioma) were enrolled in the study, all of which were IDH wild-type and refractory cases ( At least two treatments failed).
The results show that the treatment has high safety, treatment-related adverse reactions are mild, and no treatment-related grade 3 to 4 adverse reactions or signs of virus replication in the body are found; the median survival time of patients after receiving treatment is 12.
2 months, which is obvious It is 5.
6 months longer than the historical control group, suggesting that the treatment may have a good therapeutic effect.
Four patients with overall survival of G207 treatment underwent biopsy after treatment.
The study used immunohistochemistry to compare the changes of infiltrating lymphocytes in tumor tissues before and after treatment, and found that there was obvious T lymphocyte infiltration in the tumor after treatment, suggesting that the treatment has the effect of improving the "cold" immune microenvironment of glioma.
However, the above conclusions are relatively preliminary, and it is necessary to use methods such as flow cytometry, single-cell sequencing, transcriptome analysis, and T cell receptor sequencing in future studies to further analyze the types and functions of infiltrating immune cells.
This study also explored the imaging changes related to oncolytic virus therapy.
The results are similar to the results of the Duke University study, indicating that "multivesicular changes" are often the early imaging manifestations of effective treatment.
Similar to other immunotherapies for glioma, the problem of pseudo-progression has also greatly plagued the evaluation of the effect of oncolytic virus therapy.
The current imaging evaluation standard (iRANO) also urgently needs to introduce new imaging methods or methods to further improve the accuracy of imaging evaluation.
The imaging manifestations of patient 002 treated with G207 (modified HSV-1).
Previous studies have shown that the pre-existing protective antibodies against the virus in the body are an important factor in reducing the therapeutic effect of oncolytic viruses.
This study also found similar Phenomenon: The survival time of the 3 patients with pre-existing anti-HSV-1 antibodies was only 5.
1 months, which was much lower than the overall median survival time.
The seropositivity rate of anti-HSV-1 antibodies is as high as 70% to 90% in adults, but fortunately, it is mostly negative in children.
This also suggests that the suitable population for HSV-1 oncolytic virus treatment may be in children.
In summary, this study shows the encouraging results of HSV-1 oncolytic virus treatment in children with malignant gliomas.
Oncolytic virus treatment of childhood gliomas has high safety, and we look forward to the future phase 2-3 clinical trials.
The test further clarified its true therapeutic effect.
Studies also suggest that oncolytic viruses can effectively improve the immune microenvironment of gliomas, thereby providing new strategies for subsequent combination with other immunotherapies such as anti-PD-1/CTLA-4.
In addition, the enrolled cases in this study are all cases of supratentorial glioma.
Children’s brainstem glioma, especially diffuse endogenous pontine glioma (DIPG), is highly malignant and lacks effective treatment methods.
It is also hoped that it will be expanded in the future.
Clinical trials can also fully include this part of patients. Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade GliomasFriedman GK, Johnston JM, Bag AK, et al.
DOI: 10.
1056/NEJMoa2024947 Abstract background recurrence in children and adolescents The outcome of patients with sexual or progressive high-grade glioma is poor, with a previous median overall survival of 5.
6 months.
High-grade gliomas in children are basically immune silent or "cold" tumors, with very few tumor infiltrating lymphocytes.
In preclinical studies, children’s brain tumors are highly sensitive to the following oncolytic virus therapies: herpes simplex virus type 1 (HSV-1) G207 that has been genetically engineered to lack genes necessary for replication in normal brain tissue.
Methods We conducted a phase 1 trial of G207 using the 3+3 design.
The trial included children and adolescents who were diagnosed with recurrent or progressive supratentorial brain tumors by biopsy, and divided them into 4 dose cohorts.
Use stereotactic technology to place up to 4 intratumoral catheters for the patient.
The patient received G207 (107 or 108 plaque forming units) administration on the second day.
During the administration, the input rate was controlled so that the administration time lasted for 6 hours.
Patients in cohorts 3 and 4 received gross tumor target radiotherapy (5 Gy) within 24 hours after G207 administration.
This test uses culture and polymerase chain reaction to evaluate the virus excretion through saliva, conjunctiva and blood.
The tumor-infiltrating lymphocytes of the corresponding tissue samples before and after treatment were examined by immunohistochemical methods.
Results Twelve patients with high-grade glioma aged 7-18 years received G207 treatment.
No dose-limiting toxic effects or serious adverse events were attributed to G207 by the investigator.
There are 20 grade 1 adverse events that may be related to G207.
No virus excretion was detected.
In this trial, 11 patients were observed to achieve imaging, neuropathology, or clinical remission.
The median overall survival was 12.
2 months (95% confidence interval, 8.
0~16.
4); as of June 5, 2020, 18 months after G207 treatment, 4 out of 11 patients were still alive.
G207 significantly increased the number of tumor infiltrating lymphocytes.
Conclusion After patients with recurrent or progressive high-grade glioma in children received intratumoral administration of G207 and combined radiotherapy with G207, the adverse events were acceptable, and there is evidence that the patient achieved remission.
G207 transforms immune "cold" tumors into "hot" tumors.
(Funded by the US Food and Drug Administration, etc.
; registered in ClinicalTrials.
gov as NCT02457845.
) The author introduces Zhang Liwei, chief physician, second-level professor, doctoral supervisor, and expert enjoying special allowances from the State Council.
He is currently the deputy dean of Beijing Tiantan Hospital and the deputy director of the National Neurological Diseases Clinical Research Center.
He is the president of the Neurosurgery Branch of the Chinese Medical Doctor Association, the executive member of the World Society of Skull Base Surgery (WFSBS), and the executive member of the World Society of Neurosurgery (WFNS) Skull Base Surgery Committee.
He is the editor-in-chief of "NEUROSURGERY" magazine Chinese edition oncology section, deputy editor-in-chief of "Chinese Journal of Neurosurgery" and editorial board member of several publications.
He has made important contributions to the basic research and clinical work of neurosurgery complex diseases of brain stem and skull base tumors.
He has published more than 200 papers and 9 monographs in Nature Genetics, Acta Neuropathologica, Nature Communications, British Medical Journal and other journals.
Won 8 science and technology awards including the National Science and Technology Progress Award.
Cultivate more than 40 master and doctoral students.
Zhang Yang, Deputy Chief Physician of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University.
Graduated from the 11-year clinical medicine program of Peking Union Medical College in 2011, completed the doctoral research training in clinical proteomics and tumor immune microenvironment, and obtained MD and PhD degrees.
In the same year, he entered the Department of Neurosurgery of Beijing Tiantan Hospital to engage in clinical work.
His main research areas are the development of new diagnosis and treatment technologies for glioma and immunotherapy.
From June 2018 to June 2019, he completed the clinical translational study of T cell immunotherapy for glioma in the Department of Immunology of Duke University in the United States.
Presided over and participated in 8 national, provincial and ministerial-level projects, and is currently participating in 3 clinical trials of glioma immunotherapy.
He has published more than 10 first author SCI articles and participated in the editing of 3 monographs.
Copyright information This article was translated, written or commissioned by the "NEJM Frontiers of Medicine" jointly created by the Jiahui Medical Research and Education Group (J-Med) and the "New England Journal of Medicine" (NEJM).
The Chinese translation of the full text and the included diagrams are exclusively authorized by the NEJM Group.
If you need to reprint, please leave a message or contact nejmqianyan@nejmqianyan.
cn.
Unauthorized translation is an infringement, and the copyright owner reserves the right to pursue legal liabilities.
