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Childhood high-grade glioma (pHGG) is a primary malignant brain tumor with high heterogeneity derived from glial stem cells or progenitor cells, with an annual incidence of 10 parts per million.
Studies have found that high-grade gliomas in children are significantly different from adult gliomas, but have a highly aggressive clinical behavior similar to adult gliomas.
In recent decades, the research on other childhood tumors has made rapid progress.
The overall 5-year survival rate has increased to more than 80%, and childhood leukemia has even reached more than 90%.
Regrettably, the median survival time of children with pHGG is only about 12 months, and the 2-year survival rate is 10-30%, which has remained unchanged for decades.
A few days ago, NEJM published important results on high-grade glioma oncolytic virus immunotherapy in children.
Professor Zhang Yizhu's team from the Pediatric Oncology Department of Sun Yat-sen University Cancer Center reviewed this study.
Expert Profile Professor Zhang Yizhuo, Chief Physician, PhD Supervisor, Director of the Pediatric Oncology Department, Sun Yat-sen University Cancer Prevention and Treatment Center, South China National Key Laboratory of Oncology Research Group Leader, China Anti-Cancer Association Hematology Transformation Research Professional Committee Deputy Chairman CSCO China Member of the Standing Committee of the Anti-Lymphoma Alliance CSCO China Anti-Lymphoma Alliance, Executive Deputy Leader of the Children and Adolescents Group, Member of the Standing Committee of the Child Oncology Professional Committee of the Chinese Research Hospital Association Member of the Standing Committee of the Hematological Oncology Professional Committee of the Chinese Anti-Cancer Association (fourth and fifth) Chinese female physician Member of the Standing Committee of the Association's Hematology Committee Member of the Pediatric Oncology Committee of the Chinese Anti-Cancer Association Member of the Pediatric Oncology Committee of the Chinese Anti-Cancer Association Deputy Leader of the New Technology Development Group for Children's Tumors CSCO Member of the Chinese Anti-Leukemia Alliance Member of the Hematology Immunology Professional Committee of the Chinese Society of Immunology, Guangdong Province Member of the Standing Committee of the Society of Hematology of the Society of Hematology, Guangdong Anti-Cancer Association, Zhang Lian, Member of the Standing Committee of the Children’s Oncology Committee of the Guangdong Anti-Cancer Association Postdoctoral Fellow, Department of Child Oncology, Sun Yat-sen University Cancer Prevention Center, Ph.
D.
, Xiangya School of Medicine, Central South University, worked in the Norris Comprehensive Cancer Center of the University of Southern California during his Ph.
D.
Genetics experimental research, mainly responsible for children's high-grade glioma and liver cancer projects.
The laboratory has a high reputation in the field of tumor epigenetics, and is mainly engaged in basic scientific research and clinical translational research.
Children's brain tumors have become the second largest childhood tumor, second only to childhood leukemia.
High-grade glioma in children is a rapidly progressing and fatal brain tumor, accounting for about 8-10% of intracranial tumors in children.
After standard radiotherapy and chemotherapy treatment, the 3-year event-free survival rate of children was 11-22%, and the median survival time after recurrence was only 5.
6 months.
Limited by the special group of children and the overall lag in research on new treatments for brain malignancies, these numbers have not improved in recent decades.
Therefore, there is an urgent need to develop new and more effective therapies for high-grade gliomas in children.
In recent years, oncolytic viruses have attracted much attention in the immunotherapy of malignant tumors.
They can dissolve tumors to release antigens, activate immune signal pathways, and up-regulate the expression of antigen presentation molecules to promote the recognition of tumor cells by immune effector cells and promote cytotoxicity.
The infiltration of T lymphocytes and the secretion of cytokines can play the biological killing function of immune cells, improve the tumor microenvironment, enhance the effectiveness of PD-1 antibodies, and exert anti-tumor effects.
In 2017, Cell published a phase 1b clinical trial for the treatment of adult melanoma by the Jonsson Comprehensive Cancer Research Center at the University of California, Los Angeles, using gene editing tools to modify the type 1 herpes simplex virus (HSV-1).
The results showed that 62% of patients achieved clinical remission after treatment, and the complete remission rate was 33%, indicating that such patients can survive for a long time.
This study reflects the promising application prospects of oncolytic virus immunotherapy in the treatment of adult malignant tumors.
This research was led by the University of Alabama at Birmingham.
The research team used the oncolytic virus HSV-1 to try to treat patients with pHGG.
HSV-1 is naturally neurotropic, so it is suitable for the treatment of brain tumors such as pHGG.
Researchers used gene editing tools to modify the virus to remove its neurotoxicity and replication ability, and improve the safety of clinical applications.
The research team adopted the "3+3" open, non-randomized phase 1 clinical trial design.
The enrolled patients were 3 to 18 years old who were pathologically confirmed as recurrent supratentorial high-grade gliomas (10 cases of glioblastoma, 1 Cases of anaplastic astrocytoma and 1 case of high-grade glioma), all cases were IDH wild-type.
The inclusion criteria included children with tumors greater than 1.
0 cm in diameter and who had multiple recurrences after comprehensive treatment such as surgery, radiotherapy or chemotherapy.
The main purpose of this study is to evaluate the safety of 4 treatment options (107 PFU, 108 PFU, 107 PFU+5 Gy radiotherapy, 108 PFU+5 Gy radiotherapy); the secondary purpose is to study the preliminary clinical effects and biological effects of intratumoral administration.
Learn to respond. The results of this study show that oncolytic virus immunotherapy has good safety in children with high-grade gliomas, no serious adverse reactions or signs of virus replication in the body, and treatment-related side effects are slightly controllable; the median of patients The survival time was significantly extended to 12.
2 months, indicating that oncolytic virus immunotherapy has good clinical application prospects.
Figure 1 Survival time This study performed immunohistochemical analysis on the tumor samples of 4 patients to compare and analyze the changes of infiltrating lymphocytes in the tumor tissues of the children before and after treatment.
The study found that the infiltration of CD8+ T lymphocytes in the tumor was significantly increased after treatment.
This result indicates that the therapy may improve the immune microenvironment of gliomas and transform the "cold tumors" such as pHGG into "hot tumors".
However, the study also mentioned that the result may be a general inflammatory response, and it is necessary to use comprehensive sequencing analysis methods such as flow cytometry and T cell receptor sequencing to further clarify the function of immune cells in the tumor.
Figure 2 The imaging changes of intracranial lesions in children before and after treatment.
The research team used magnetic resonance imaging (MRI) to compare the imaging changes of intracranial lesions in children before and after treatment.
Studies have found that "multivesicular changes" are an early imaging manifestation of effective oncolytic virus immunotherapy.
Similar to other immunotherapies for glioma, the problem of pseudo-progression also greatly puzzles the evaluation of the effectiveness of oncolytic virus therapy.
Therefore, it is urgent to adopt multi-dimensional imaging evaluation methods to improve the accuracy of evaluation.
At the same time, previous studies have shown that the antiviral antibodies originally present in patients can reduce the efficacy of immunotherapy.
This study also confirmed this phenomenon.
The median survival time of the 3 children with HSV-1 protective antibodies was only about 5 months, which was much lower than the average.
Fortunately, compared with adults, the HSV-1 antibody in children's body fluids is mostly negative, which also suggests that this type of therapy has better application value in children with tumors.
The conclusion of this important study is: oncolytic virus immunotherapy has better safety in children with high-grade gliomas, and this therapy can increase the infiltration of immune cells in the tumor and improve the immune microenvironment, thus combining PD- 1 Immune checkpoint inhibitors such as antibodies provide a theoretical basis and exert anti-tumor synergistic effects.
We look forward to future studies that can provide better treatment options.
Comment 1: High-grade glioma in children is a rapidly progressing and fatal brain tumor.
There is currently no effective treatment.
The median survival time of children after recurrence is only 5 months.
The current frontier research in research mainly includes CAR-T, oncolytic virus immunotherapy, monoclonal antibodies, epigenetic therapy, etc.
, but none of them has been applied in clinical practice.
This study was led by the University of Alabama at Birmingham, and it was the first clinical trial using the oncolytic virus HSV-1 in patients with pHGG.
HSV-1 is naturally neurophilic and is suitable for the treatment of brain tumors such as pHGG.
Researchers used gene editing tools to modify the virus to remove its neurotoxicity and replication ability, and improve the safety of clinical applications.
Two: The study used magnetic resonance imaging (MRI) to evaluate the imaging changes of intracranial lesions in children before and after treatment.
Studies have found that "multivesicular changes" are an effective imaging manifestation of oncolytic virus therapy.
However, the problem of false progress often confuses the evaluation of imaging efficacy and may cause misdiagnosis.
Therefore, introducing new imaging methods and adopting a multi-dimensional evaluation method can effectively improve the accuracy of the evaluation.
Three: The results of this study found that intratumoral injection of oncolytic virus can significantly increase the degree of CD8+ T lymphocyte infiltration, indicating that this therapy can improve the immune microenvironment of gliomas and turn "cold tumors" such as pHGG into "hot tumors" Role, so as to provide a theoretical basis for the follow-up combination of immune checkpoint inhibitors such as PD-1.
It is worth noting that the results of this study did not in-depth study of relevant immune response molecules, cytokines, etc.
, and may only be general inflammatory reactions.
It is necessary to use flow cytometry and T cell receptor sequencing in the next research.
And other comprehensive sequencing analysis methods further clarify the function of immune cells in the tumor.
Four: The study found that the oncolytic virus antibodies originally present in the child's body can reduce the therapeutic effect.
However, compared with adults, the antiviral antibodies in children's body fluids are mostly negative, which also suggests that this therapy has better application value in children.
The fly in the ointment is that the children included in the study are all cases of supratentorial glioma, and pHGG, which occurs in dangerous sites such as the brain stem and has a higher degree of malignancy, especially diffuse endogenous pontine glioma (DIPG), Its five-year survival rate is less than 1%, and there is currently a lack of effective treatments.
It is hoped that future clinical trials can benefit these patients.
Reference: Friedman, GK et al.
Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.
The New England journal of medicine, doi:10.
1056/NEJMoa2024947 (2021).
Studies have found that high-grade gliomas in children are significantly different from adult gliomas, but have a highly aggressive clinical behavior similar to adult gliomas.
In recent decades, the research on other childhood tumors has made rapid progress.
The overall 5-year survival rate has increased to more than 80%, and childhood leukemia has even reached more than 90%.
Regrettably, the median survival time of children with pHGG is only about 12 months, and the 2-year survival rate is 10-30%, which has remained unchanged for decades.
A few days ago, NEJM published important results on high-grade glioma oncolytic virus immunotherapy in children.
Professor Zhang Yizhu's team from the Pediatric Oncology Department of Sun Yat-sen University Cancer Center reviewed this study.
Expert Profile Professor Zhang Yizhuo, Chief Physician, PhD Supervisor, Director of the Pediatric Oncology Department, Sun Yat-sen University Cancer Prevention and Treatment Center, South China National Key Laboratory of Oncology Research Group Leader, China Anti-Cancer Association Hematology Transformation Research Professional Committee Deputy Chairman CSCO China Member of the Standing Committee of the Anti-Lymphoma Alliance CSCO China Anti-Lymphoma Alliance, Executive Deputy Leader of the Children and Adolescents Group, Member of the Standing Committee of the Child Oncology Professional Committee of the Chinese Research Hospital Association Member of the Standing Committee of the Hematological Oncology Professional Committee of the Chinese Anti-Cancer Association (fourth and fifth) Chinese female physician Member of the Standing Committee of the Association's Hematology Committee Member of the Pediatric Oncology Committee of the Chinese Anti-Cancer Association Member of the Pediatric Oncology Committee of the Chinese Anti-Cancer Association Deputy Leader of the New Technology Development Group for Children's Tumors CSCO Member of the Chinese Anti-Leukemia Alliance Member of the Hematology Immunology Professional Committee of the Chinese Society of Immunology, Guangdong Province Member of the Standing Committee of the Society of Hematology of the Society of Hematology, Guangdong Anti-Cancer Association, Zhang Lian, Member of the Standing Committee of the Children’s Oncology Committee of the Guangdong Anti-Cancer Association Postdoctoral Fellow, Department of Child Oncology, Sun Yat-sen University Cancer Prevention Center, Ph.
D.
, Xiangya School of Medicine, Central South University, worked in the Norris Comprehensive Cancer Center of the University of Southern California during his Ph.
D.
Genetics experimental research, mainly responsible for children's high-grade glioma and liver cancer projects.
The laboratory has a high reputation in the field of tumor epigenetics, and is mainly engaged in basic scientific research and clinical translational research.
Children's brain tumors have become the second largest childhood tumor, second only to childhood leukemia.
High-grade glioma in children is a rapidly progressing and fatal brain tumor, accounting for about 8-10% of intracranial tumors in children.
After standard radiotherapy and chemotherapy treatment, the 3-year event-free survival rate of children was 11-22%, and the median survival time after recurrence was only 5.
6 months.
Limited by the special group of children and the overall lag in research on new treatments for brain malignancies, these numbers have not improved in recent decades.
Therefore, there is an urgent need to develop new and more effective therapies for high-grade gliomas in children.
In recent years, oncolytic viruses have attracted much attention in the immunotherapy of malignant tumors.
They can dissolve tumors to release antigens, activate immune signal pathways, and up-regulate the expression of antigen presentation molecules to promote the recognition of tumor cells by immune effector cells and promote cytotoxicity.
The infiltration of T lymphocytes and the secretion of cytokines can play the biological killing function of immune cells, improve the tumor microenvironment, enhance the effectiveness of PD-1 antibodies, and exert anti-tumor effects.
In 2017, Cell published a phase 1b clinical trial for the treatment of adult melanoma by the Jonsson Comprehensive Cancer Research Center at the University of California, Los Angeles, using gene editing tools to modify the type 1 herpes simplex virus (HSV-1).
The results showed that 62% of patients achieved clinical remission after treatment, and the complete remission rate was 33%, indicating that such patients can survive for a long time.
This study reflects the promising application prospects of oncolytic virus immunotherapy in the treatment of adult malignant tumors.
This research was led by the University of Alabama at Birmingham.
The research team used the oncolytic virus HSV-1 to try to treat patients with pHGG.
HSV-1 is naturally neurotropic, so it is suitable for the treatment of brain tumors such as pHGG.
Researchers used gene editing tools to modify the virus to remove its neurotoxicity and replication ability, and improve the safety of clinical applications.
The research team adopted the "3+3" open, non-randomized phase 1 clinical trial design.
The enrolled patients were 3 to 18 years old who were pathologically confirmed as recurrent supratentorial high-grade gliomas (10 cases of glioblastoma, 1 Cases of anaplastic astrocytoma and 1 case of high-grade glioma), all cases were IDH wild-type.
The inclusion criteria included children with tumors greater than 1.
0 cm in diameter and who had multiple recurrences after comprehensive treatment such as surgery, radiotherapy or chemotherapy.
The main purpose of this study is to evaluate the safety of 4 treatment options (107 PFU, 108 PFU, 107 PFU+5 Gy radiotherapy, 108 PFU+5 Gy radiotherapy); the secondary purpose is to study the preliminary clinical effects and biological effects of intratumoral administration.
Learn to respond. The results of this study show that oncolytic virus immunotherapy has good safety in children with high-grade gliomas, no serious adverse reactions or signs of virus replication in the body, and treatment-related side effects are slightly controllable; the median of patients The survival time was significantly extended to 12.
2 months, indicating that oncolytic virus immunotherapy has good clinical application prospects.
Figure 1 Survival time This study performed immunohistochemical analysis on the tumor samples of 4 patients to compare and analyze the changes of infiltrating lymphocytes in the tumor tissues of the children before and after treatment.
The study found that the infiltration of CD8+ T lymphocytes in the tumor was significantly increased after treatment.
This result indicates that the therapy may improve the immune microenvironment of gliomas and transform the "cold tumors" such as pHGG into "hot tumors".
However, the study also mentioned that the result may be a general inflammatory response, and it is necessary to use comprehensive sequencing analysis methods such as flow cytometry and T cell receptor sequencing to further clarify the function of immune cells in the tumor.
Figure 2 The imaging changes of intracranial lesions in children before and after treatment.
The research team used magnetic resonance imaging (MRI) to compare the imaging changes of intracranial lesions in children before and after treatment.
Studies have found that "multivesicular changes" are an early imaging manifestation of effective oncolytic virus immunotherapy.
Similar to other immunotherapies for glioma, the problem of pseudo-progression also greatly puzzles the evaluation of the effectiveness of oncolytic virus therapy.
Therefore, it is urgent to adopt multi-dimensional imaging evaluation methods to improve the accuracy of evaluation.
At the same time, previous studies have shown that the antiviral antibodies originally present in patients can reduce the efficacy of immunotherapy.
This study also confirmed this phenomenon.
The median survival time of the 3 children with HSV-1 protective antibodies was only about 5 months, which was much lower than the average.
Fortunately, compared with adults, the HSV-1 antibody in children's body fluids is mostly negative, which also suggests that this type of therapy has better application value in children with tumors.
The conclusion of this important study is: oncolytic virus immunotherapy has better safety in children with high-grade gliomas, and this therapy can increase the infiltration of immune cells in the tumor and improve the immune microenvironment, thus combining PD- 1 Immune checkpoint inhibitors such as antibodies provide a theoretical basis and exert anti-tumor synergistic effects.
We look forward to future studies that can provide better treatment options.
Comment 1: High-grade glioma in children is a rapidly progressing and fatal brain tumor.
There is currently no effective treatment.
The median survival time of children after recurrence is only 5 months.
The current frontier research in research mainly includes CAR-T, oncolytic virus immunotherapy, monoclonal antibodies, epigenetic therapy, etc.
, but none of them has been applied in clinical practice.
This study was led by the University of Alabama at Birmingham, and it was the first clinical trial using the oncolytic virus HSV-1 in patients with pHGG.
HSV-1 is naturally neurophilic and is suitable for the treatment of brain tumors such as pHGG.
Researchers used gene editing tools to modify the virus to remove its neurotoxicity and replication ability, and improve the safety of clinical applications.
Two: The study used magnetic resonance imaging (MRI) to evaluate the imaging changes of intracranial lesions in children before and after treatment.
Studies have found that "multivesicular changes" are an effective imaging manifestation of oncolytic virus therapy.
However, the problem of false progress often confuses the evaluation of imaging efficacy and may cause misdiagnosis.
Therefore, introducing new imaging methods and adopting a multi-dimensional evaluation method can effectively improve the accuracy of the evaluation.
Three: The results of this study found that intratumoral injection of oncolytic virus can significantly increase the degree of CD8+ T lymphocyte infiltration, indicating that this therapy can improve the immune microenvironment of gliomas and turn "cold tumors" such as pHGG into "hot tumors" Role, so as to provide a theoretical basis for the follow-up combination of immune checkpoint inhibitors such as PD-1.
It is worth noting that the results of this study did not in-depth study of relevant immune response molecules, cytokines, etc.
, and may only be general inflammatory reactions.
It is necessary to use flow cytometry and T cell receptor sequencing in the next research.
And other comprehensive sequencing analysis methods further clarify the function of immune cells in the tumor.
Four: The study found that the oncolytic virus antibodies originally present in the child's body can reduce the therapeutic effect.
However, compared with adults, the antiviral antibodies in children's body fluids are mostly negative, which also suggests that this therapy has better application value in children.
The fly in the ointment is that the children included in the study are all cases of supratentorial glioma, and pHGG, which occurs in dangerous sites such as the brain stem and has a higher degree of malignancy, especially diffuse endogenous pontine glioma (DIPG), Its five-year survival rate is less than 1%, and there is currently a lack of effective treatments.
It is hoped that future clinical trials can benefit these patients.
Reference: Friedman, GK et al.
Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas.
The New England journal of medicine, doi:10.
1056/NEJMoa2024947 (2021).
