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Malignant high-grade glioma is a common brain tumor in children, with a very high fatality rate and a very poor prognosis.
Due to the lack of effective treatments, the survival rate of patients has not improved significantly in the past 30 years.
Among patients receiving standard radiotherapy and chemotherapy, the 3-year event-free survival is only 11-22%, and the average life expectancy of relapsed patients is only 5.
6 months [1, 2].
Therefore, innovative treatment methods are urgently needed.
Recently, a research team led by Professor Gregory Friedman of the Department of Pediatrics at the University of Labama at Birmingham published a phase I clinical trial of HSV-1 G207 oncolytic virus in the treatment of recurrent high-grade glioma in children in the New England Journal of Medicine.
Trial (NCT02457845) research data, the study found that G207 alone or in combination with radiotherapy significantly improved the prognosis of children with good safety and tolerability [3].
"This is the first study to directly apply viral immunotherapy to children's brain tumors.
" Dr.
Friedman said, "Our research results show that G207 can safely enter tumors in all areas of the brain, and the therapy is safe and resistant.
Receptive.
"In other words, children with refractory malignant high-grade gliomas are expected to usher in a new treatment method.
The oncolytic HSV-1 G207 is currently one of the most comprehensively studied viruses.
After a series of modifications, G207 loses its ability to infect normal cells, but it can infect tumor cells and replicate conditionally in tumor cells.
Ability.
In other words, G207 can lyse tumor cells without damaging normal cells [4].
In addition, G207 can also reverse tumor immune escape, increase the cross-presentation of tumor antigens, and promote anti-tumor immune responses [5-8].
G207 has the characteristics of neurotoxicity, making brain tumors an ideal target.
G207 can bypass the blood-brain barrier through intratumoral inoculation.
Because it retains the thymidine kinase gene, it is sensitive to antiviral drugs.
Once viral encephalitis occurs, antiviral drugs can be used for intervention.
In fact, in a number of previous clinical trials of adult high-grade glioma, researchers have demonstrated the safety and tolerability of G207 [9-11], but the response of pediatric patients to G207 is different from that of adults.
Its effectiveness and safety in children with high-grade glioma are still unclear.
This open-label, non-randomized phase I trial initiated by Professor Friedman, the antivirus mechanism of oncolytic viruses, uses a 3+3 design method and includes 4 dose groups: 107 PFU, 108 PFU, 107 PFU+5Gy radiotherapy and 108 PFU+5Gy radiotherapy , Where the G207 injection dose is determined based on the data of the adult phase I trial.
Next, let's take a look at the test results together.
Between October 2016 and April 2020, a total of 13 patients underwent eligibility assessment, of which 12 patients (6 males and 6 females, age range 7-18 years) with progressive or recurrent episodes Upper high-grade glioma meets the inclusion criteria, with 3 patients in each group.
Before G207 treatment, most patients had received other treatments.
Among them, 8 patients had at least two treatment failure experiences, and 4 patients had at least three treatment failure experiences.
In order to inject G207 into a child's intracranial tumor, the researchers implanted an internal catheter in the child's brain according to the tumor location.
Subsequently, the researchers will infuse G207 into the brain through a catheter within 6 hours, and the total volume of the inoculation is 2.
4ml.
In the latter two dose groups, within 24 hours after G207 inoculation, the tumor and its surrounding 2mm edge also need to receive a single 5Gy radiation dose of radiotherapy.
Among the 44 catheters placed, no neurological sequelae during the operation were observed.
Flow chart of the study protocol Within 30 days after the end of treatment, all patients reported a total of 20 grade 1 adverse events related to G207, mainly nausea, vomiting, diarrhea and fatigue, and no grade 3-4 toxic reactions related to G207 were found.
Or serious adverse events.
In addition, no evidence of peripheral G207 shedding or viremia was found in all patients.
11 patients had radiological, neuropathological or clinical reactions, and the median overall survival was 12.
2 months (95% confidence interval 8.
0 to 16.
4), which was higher than the typical overall survival of progressive pediatric high-grade glioma (5.
6 Month) increased by 120%.
As of June 5, 2020, 4 out of 11 patients (36%) were still alive after 18 months of G207 treatment, exceeding the expected survival rate for children newly diagnosed with high-grade glioma.
Kaplan-Meier curve of the overall survival probability of patients receiving G207 treatment.
In addition, in four patients who received tissue biopsy or resection after treatment, the researchers evaluated the T lymphocytes in matched tumor tissues before and after treatment through immunohistochemical analysis.
content.
They found that there were few tumor infiltrating lymphocytes in the tumor tissues before treatment.
On the contrary, the tumor tissues of patients in each dose group increased significantly in CD3+, CD4+ and CD8+ tumor tissues after 2 to 9 months of treatment.
Shows that G207 induces a strong local immune response to use the body's immune system to further fight tumor cells.
Immunohistochemical staining of CD8+ T lymphocytes in matched tissues of 4 patients before and after treatment.
In general, the data of the study showed that G207 alone or in combination with radiotherapy is safe and potentially effective in the treatment of high-grade gliomas in children, and only produces low-grade gliomas.
, Acceptable toxicity.
G207 can induce a large increase in tumor-infiltrating lymphocytes, and can transform childhood high-grade gliomas, which are immune "cold" tumors with few immune cells, into "hot" tumors with abundant immune cells.
This will be a high-grade glioma for children.
New research and development direction of tumor immunotherapy.
However, the data in this study are only preliminary results of the phase I research phase, and phase II clinical trials are needed to further support the effectiveness of G207 in the treatment of recurrent high-grade gliomas in children.
At present, the Phase II clinical trial of G207 for the treatment of recurrent high-grade glioma in children is in the late stage of the plan.
It is expected to start the phase II clinical trial later in 2021, which will provide a new option for the treatment of high-grade glioma in children.
Program. References: [1].
Jakacki RI, Cohen KJ, Buxton A, et al.
Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study.
Neuro Oncol.
2016;18(10):1442-1450.
doi:10.
1093/neuonc/now038[2].
Kline C, Felton E, Allen IE, Tahir P, Mueller S.
Survival outcomes in pediatric recurrent high- grade glioma: results of a 20-year systematic review and meta-analysis.
J Neurooncol.
2018;137(1):103-110.
doi:10.
1007/s11060-017-2701-8[3].
Friedman GK, Johnston JM , Bag AK, et al.
Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas [published online ahead of print, 2021 Apr 10].
N Engl J Med.
2021;10.
1056/NEJMoa2024947.
doi:10.
1056/NEJMoa2024947[4] .
Goldstein DJ, Weller SK.
Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: isolation and characterization of an ICP6 lacZ insertion mutant.
J Virol.
1988;62(1):196-205.
doi:10.
1128/JVI.
62.
1 .
196-205.
1988[5].
Toda M, Rabkin SD, Kojima H, Martuza RL.
Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity.
Hum Gene Ther.
1999;10(3): 385-393.
doi:10.
1089/10430349950018832[6].
Todo T, Rabkin SD, Sundaresan P, et al.
Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus.
Hum Gene Ther.
1999; 10(17):2741-2755.
doi:10.
1089/10430349950016483[7].
Benencia F, Courrèges MC, Fraser NW, Coukos G.
Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation.
Cancer Biol Ther.
2008;7(8):1194-1205.
doi:10.
4161/cbt.
7.
8.
6216[8].
Leddon JL, Chen CY, Currier MA , et al.
Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity.
Mol Ther Oncolytics.
2015;1:14010.
Published 2015 Jan 21.
doi:10.
1038/mto.
2014.
10[9] Markert JM, Medlock MD, Rabkin SD, et al.
Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial.
Gene Ther.
2000;7(10):867-874.
doi :10.
1038/sj.
gt.
3301205[10].
Markert JM, Liechty PG, Wang W, et al.
Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM.
Mol Ther.
2009; 17(1):199-207.
doi:10.
1038/mt.
2008.
228[11].
Markert JM, Razdan SN, Kuo HC, et al.
A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses.
Mol Ther.
2014;22(5):1048-1055.
doi:10.
1038/mt.
2014.
22 Author of this articleResponsible editor of Hami MelonBioTalker
Due to the lack of effective treatments, the survival rate of patients has not improved significantly in the past 30 years.
Among patients receiving standard radiotherapy and chemotherapy, the 3-year event-free survival is only 11-22%, and the average life expectancy of relapsed patients is only 5.
6 months [1, 2].
Therefore, innovative treatment methods are urgently needed.
Recently, a research team led by Professor Gregory Friedman of the Department of Pediatrics at the University of Labama at Birmingham published a phase I clinical trial of HSV-1 G207 oncolytic virus in the treatment of recurrent high-grade glioma in children in the New England Journal of Medicine.
Trial (NCT02457845) research data, the study found that G207 alone or in combination with radiotherapy significantly improved the prognosis of children with good safety and tolerability [3].
"This is the first study to directly apply viral immunotherapy to children's brain tumors.
" Dr.
Friedman said, "Our research results show that G207 can safely enter tumors in all areas of the brain, and the therapy is safe and resistant.
Receptive.
"In other words, children with refractory malignant high-grade gliomas are expected to usher in a new treatment method.
The oncolytic HSV-1 G207 is currently one of the most comprehensively studied viruses.
After a series of modifications, G207 loses its ability to infect normal cells, but it can infect tumor cells and replicate conditionally in tumor cells.
Ability.
In other words, G207 can lyse tumor cells without damaging normal cells [4].
In addition, G207 can also reverse tumor immune escape, increase the cross-presentation of tumor antigens, and promote anti-tumor immune responses [5-8].
G207 has the characteristics of neurotoxicity, making brain tumors an ideal target.
G207 can bypass the blood-brain barrier through intratumoral inoculation.
Because it retains the thymidine kinase gene, it is sensitive to antiviral drugs.
Once viral encephalitis occurs, antiviral drugs can be used for intervention.
In fact, in a number of previous clinical trials of adult high-grade glioma, researchers have demonstrated the safety and tolerability of G207 [9-11], but the response of pediatric patients to G207 is different from that of adults.
Its effectiveness and safety in children with high-grade glioma are still unclear.
This open-label, non-randomized phase I trial initiated by Professor Friedman, the antivirus mechanism of oncolytic viruses, uses a 3+3 design method and includes 4 dose groups: 107 PFU, 108 PFU, 107 PFU+5Gy radiotherapy and 108 PFU+5Gy radiotherapy , Where the G207 injection dose is determined based on the data of the adult phase I trial.
Next, let's take a look at the test results together.
Between October 2016 and April 2020, a total of 13 patients underwent eligibility assessment, of which 12 patients (6 males and 6 females, age range 7-18 years) with progressive or recurrent episodes Upper high-grade glioma meets the inclusion criteria, with 3 patients in each group.
Before G207 treatment, most patients had received other treatments.
Among them, 8 patients had at least two treatment failure experiences, and 4 patients had at least three treatment failure experiences.
In order to inject G207 into a child's intracranial tumor, the researchers implanted an internal catheter in the child's brain according to the tumor location.
Subsequently, the researchers will infuse G207 into the brain through a catheter within 6 hours, and the total volume of the inoculation is 2.
4ml.
In the latter two dose groups, within 24 hours after G207 inoculation, the tumor and its surrounding 2mm edge also need to receive a single 5Gy radiation dose of radiotherapy.
Among the 44 catheters placed, no neurological sequelae during the operation were observed.
Flow chart of the study protocol Within 30 days after the end of treatment, all patients reported a total of 20 grade 1 adverse events related to G207, mainly nausea, vomiting, diarrhea and fatigue, and no grade 3-4 toxic reactions related to G207 were found.
Or serious adverse events.
In addition, no evidence of peripheral G207 shedding or viremia was found in all patients.
11 patients had radiological, neuropathological or clinical reactions, and the median overall survival was 12.
2 months (95% confidence interval 8.
0 to 16.
4), which was higher than the typical overall survival of progressive pediatric high-grade glioma (5.
6 Month) increased by 120%.
As of June 5, 2020, 4 out of 11 patients (36%) were still alive after 18 months of G207 treatment, exceeding the expected survival rate for children newly diagnosed with high-grade glioma.
Kaplan-Meier curve of the overall survival probability of patients receiving G207 treatment.
In addition, in four patients who received tissue biopsy or resection after treatment, the researchers evaluated the T lymphocytes in matched tumor tissues before and after treatment through immunohistochemical analysis.
content.
They found that there were few tumor infiltrating lymphocytes in the tumor tissues before treatment.
On the contrary, the tumor tissues of patients in each dose group increased significantly in CD3+, CD4+ and CD8+ tumor tissues after 2 to 9 months of treatment.
Shows that G207 induces a strong local immune response to use the body's immune system to further fight tumor cells.
Immunohistochemical staining of CD8+ T lymphocytes in matched tissues of 4 patients before and after treatment.
In general, the data of the study showed that G207 alone or in combination with radiotherapy is safe and potentially effective in the treatment of high-grade gliomas in children, and only produces low-grade gliomas.
, Acceptable toxicity.
G207 can induce a large increase in tumor-infiltrating lymphocytes, and can transform childhood high-grade gliomas, which are immune "cold" tumors with few immune cells, into "hot" tumors with abundant immune cells.
This will be a high-grade glioma for children.
New research and development direction of tumor immunotherapy.
However, the data in this study are only preliminary results of the phase I research phase, and phase II clinical trials are needed to further support the effectiveness of G207 in the treatment of recurrent high-grade gliomas in children.
At present, the Phase II clinical trial of G207 for the treatment of recurrent high-grade glioma in children is in the late stage of the plan.
It is expected to start the phase II clinical trial later in 2021, which will provide a new option for the treatment of high-grade glioma in children.
Program. References: [1].
Jakacki RI, Cohen KJ, Buxton A, et al.
Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study.
Neuro Oncol.
2016;18(10):1442-1450.
doi:10.
1093/neuonc/now038[2].
Kline C, Felton E, Allen IE, Tahir P, Mueller S.
Survival outcomes in pediatric recurrent high- grade glioma: results of a 20-year systematic review and meta-analysis.
J Neurooncol.
2018;137(1):103-110.
doi:10.
1007/s11060-017-2701-8[3].
Friedman GK, Johnston JM , Bag AK, et al.
Oncolytic HSV-1 G207 Immunovirotherapy for Pediatric High-Grade Gliomas [published online ahead of print, 2021 Apr 10].
N Engl J Med.
2021;10.
1056/NEJMoa2024947.
doi:10.
1056/NEJMoa2024947[4] .
Goldstein DJ, Weller SK.
Herpes simplex virus type 1-induced ribonucleotide reductase activity is dispensable for virus growth and DNA synthesis: isolation and characterization of an ICP6 lacZ insertion mutant.
J Virol.
1988;62(1):196-205.
doi:10.
1128/JVI.
62.
1 .
196-205.
1988[5].
Toda M, Rabkin SD, Kojima H, Martuza RL.
Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity.
Hum Gene Ther.
1999;10(3): 385-393.
doi:10.
1089/10430349950018832[6].
Todo T, Rabkin SD, Sundaresan P, et al.
Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus.
Hum Gene Ther.
1999; 10(17):2741-2755.
doi:10.
1089/10430349950016483[7].
Benencia F, Courrèges MC, Fraser NW, Coukos G.
Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation.
Cancer Biol Ther.
2008;7(8):1194-1205.
doi:10.
4161/cbt.
7.
8.
6216[8].
Leddon JL, Chen CY, Currier MA , et al.
Oncolytic HSV virotherapy in murine sarcomas differentially triggers an antitumor T-cell response in the absence of virus permissivity.
Mol Ther Oncolytics.
2015;1:14010.
Published 2015 Jan 21.
doi:10.
1038/mto.
2014.
10[9] Markert JM, Medlock MD, Rabkin SD, et al.
Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial.
Gene Ther.
2000;7(10):867-874.
doi :10.
1038/sj.
gt.
3301205[10].
Markert JM, Liechty PG, Wang W, et al.
Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM.
Mol Ther.
2009; 17(1):199-207.
doi:10.
1038/mt.
2008.
228[11].
Markert JM, Razdan SN, Kuo HC, et al.
A phase 1 trial of oncolytic HSV-1, G207, given in combination with radiation for recurrent GBM demonstrates safety and radiographic responses.
Mol Ther.
2014;22(5):1048-1055.
doi:10.
1038/mt.
2014.
22 Author of this articleResponsible editor of Hami MelonBioTalker
