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Introduction Viruses, people talk about it
.
In the long years of fighting the virus, people have developed a variety of drugs to fight against it, saving countless lives
.
Driven by coincidence and technological revolution, people discovered the possibility of "domesticating" the virus and using it for tumor treatment
.
Yimaitong invited Professor Wang Baocheng from the 960th Hospital of the People's Liberation Army to share with us the development history and mechanism of oncolytic viruses
.
Professor Wang Baocheng Chief Physician and Doctoral Tutor of the People’s Liberation Army 960 Hospital (formerly the General Hospital of Jinan Military Command), former Director of the Oncology Institute of Jinan Military Command, former Director of the Institute of Oncology of Jinan Military Command, Executive Director of the Chinese Society of Clinical Oncology (CSCO), CSCO Immunotherapy Committee Chairman, CSCO Anti- Oncology Drug Safety Management Expert Committee Standing Committee Member CSCO Liver Cancer Expert Committee Standing Committee CSCO Malignant Melanoma Expert Committee Standing Committee Member of the All Army Oncology Professional Committee Vice Chairman of the Central Military Commission Health Care Consultation Expert Vice Chairman of Shandong Medical Physician Association Director of the National Drug Clinical Verification Agency "China Digestion The editor-in-chief of the Journal of Diseases and Imaging, etc.
Yimaitong: In 2010, the FDA approved a series of immunotherapy drugs, opening a new era of tumor immunotherapy
.
Prior to this, tumor immunotherapy has gone through more than one hundred years of exploration.
Could you please introduce the development history of tumor immunotherapy? Professor Wang Baocheng: Tumor immunotherapy has experienced more than one hundred years of development.
It can be said that it has experienced ups and downs, and even stagnated for a while
.
However, in the past two to three decades, tumor immunotherapy has achieved rapid development and is expected to become an important weapon for curing tumors
.
Tumor immunotherapy can be roughly divided into the following stages: The first stage is the exploratory period
.
The discovery of Coley toxin represents the beginning of immunotherapy for malignant tumors
.
In 1866, German surgeon Wilhelm Busch discovered that after a patient with sarcoma was infected with erysipelas, the tumor subsided unexpectedly
.
Subsequently, New York surgeon Coley observed multiple cases of tumor regression after acute bacterial infections in tumor patients.
This discovery inspired Coley's lifelong clinical trials with bacterial filters
.
Coley uses a filtered mixture of dead Streptococcus pyogenes and Serratia marcescens to treat tumors.
This mixed vaccine is called "Coley toxin"
.
In a few patients, Coley was successful (20%)
.
However, due to the excessive toxicity of Coley toxin (mainly high fever), this treatment method has gradually faded out of people's sight
.
But Coley's contribution is a landmark, so it is also recorded in the annals of history
.
The second stage is the restructuring development period.
Immunotherapy focuses on the injection of restructured bacterial products or extracts, such as BCG and Corynebacterium parvum, into the tumor and in the body to enhance the body's non-specific immunity
.
The toxicity of this method is significantly reduced, but the curative effect is average
.
The third stage is the cytokine regulation period.
Researchers have discovered that gene recombination technology can promote the production of large amounts of cytokines in cells, which can be used for tumor treatment, such as recombinant IFN-α, IL-2, TNF, and so on
.
The fourth stage is the outbreak period
.
There are two important breakthroughs in this stage.
One is the discovery of immune checkpoints
.
American and Japanese scientists have successively discovered immune checkpoint molecules: cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), It reveals the negative immune regulation mechanism, and promotes the wide application of current immune checkpoint inhibitors
.
Therefore, the main discoverers-Professor Allison from the United States and Professor Shusuke Moto from Japan won the 2018 Nobel Prize in Physiology or Medicine
.
Another breakthrough is the development of chimeric antigen receptor T cell technology (CAR-T) and other chimeric antigen receptor immune cell technology (CAR-NK, etc.
)
.
From the end of the 20th century to the present, the clinical applications of recombinant cytokines, monoclonal antibody technology, immune cell therapy, tumor vaccines, oncolytic viruses, immune checkpoint inhibitors, etc.
, have greatly improved the clinical benefits of tumor patients and made tumor immune The treatment has entered a stage of comprehensive development
.
Yimaitong: The human immune system is the key guarantee to protect the body from external diseases
.
Could you please introduce why tumor cells can evade immune surveillance, and how does immunotherapy identify "pretenders"? Professor Wang Baocheng: Tumor cells are very cunning and use various methods to evade recognition or attack by the body's immune system.
We call this "immune escape"
.
The body's anti-tumor immune response roughly consists of 7 stages: antigen release from necrotic tumor cells, antigen capture, processing and presentation, antigen recognition and T cell activation, T cell proliferation and migration, immune cell infiltration, re-recognition and tumor killing and so on
.
Any link of these 7 steps will cause tumor immune escape.
For example, tumors can not be recognized by immune cells through the lack or change of specific antigens; tumor cells can significantly reduce the number of immune cells around the tumor by preventing the infiltration of immune cells.
The formation of a local immune "desert"; tumor cells can also up-regulate the expression of immune checkpoint molecules, such as PD-1 and PD-L1, which severely inhibit T cell function and make T cells lose their ability to kill tumors, etc.
.
A sound immune system regulates immune cells in a balanced state of activation and suppression.
If too strong, immune cells will attack their own tissues and produce autoimmune diseases, while too weak will lead to tumors
.
When a person's body is detected with tumor cells or even tumor masses, it means that the tumor cells have escaped the surveillance of the immune system
.
At this time, the body needs to restart the immune system to control malignant tumors
.
The basic principle of the effectiveness of immunotherapy against tumors is: Since the patient's body's immune checkpoints are overexpressed, immunosuppression is formed, as if a car was stepped on the brake
.
Then the injection of the immune checkpoint inhibitor will combine the inhibitor with the immune checkpoint, thereby removing the inhibitory factors, just like releasing the brakes of a car
.
Currently, the most in-depth researched immune checkpoints are PD-1/PD-L1, CTLA-4, TIM-3, LAG-3 and TIGIT
.
In addition, tumor immunotherapies also include CAR-T, tumor vaccines, oncolytic viruses, etc.
These immunotherapies have gradually become research hotspots in recent years
.
Yimaitong: You just mentioned that oncolytic virus is also an important tumor immunotherapy.
It is reported that many research advances have been made
.
Could you please introduce us the main types, anti-tumor mechanisms and characteristics of oncolytic viruses? Professor Wang Baocheng: Oncolytic viruses are a type of natural or genetically modified viruses that can selectively infect tumor cells without infecting normal cells.
They replicate in a large amount and eventually lyse tumor cells.
At the same time, they will release a large amount of tumor antigens and improve Tumor microenvironment
.
At present, dozens of oncolytic virus drugs have been developed for tumor treatment, five of which are most commonly used: adenovirus, herpes simplex virus type I (HSV-1), reovirus, vaccinia virus and Newcastle disease virus
.
Among them, two oncolytic viruses have completed phase III clinical studies as drugs and have been approved for marketing, namely H101 (recombinant human adenovirus type 5, Encore®) and T-VEC (HSV-1)
.
At present, it is believed that oncolytic viruses mainly exert anti-tumor activity through four mechanisms of action: the first is oncolytic effect.
Oncolytic viruses can replicate in tumor cells specifically and in a large amount, which is mainly due to the specificity of tumors.
Aberrations cause cell signal transduction pathways to fail to recognize and block virus replication.
At the same time, tumor cells are defective in interferon production and cannot regulate the virus defense system, resulting in the final lysis of tumor cells
.
The second is that after tumor cells are lysed, a large amount of antigens are released, which stimulates an anti-tumor immune response, and by inducing chemotaxis, it turns "cold" tumors into "hot" tumors
.
The third is anti-angiogenesis.
Oncolytic viruses can infect and destroy tumor vasculature, induce neutrophil influx, and cause vascular collapse and tumor cell death
.
The fourth is to further enhance the oncolysis effect through the modification of viruses and virus-carrying genes
.
Most oncolytic viruses used in clinical trials have undergone genetic modification, and GM-CSF is the most commonly used inserted gene
.
Compared with traditional immunotherapy, oncolytic virus drugs have good targeting, less side effects, and multiple anti-tumor pathways (such as oncolytic effect, anti-angiogenesis, stimulating anti-tumor immune response, enhanced oncolysis through genetic modification), and difficult It produces advantages such as drug resistance
.
In addition, the combination of oncolytic virus drugs and chemotherapy, radiotherapy, and immunotherapy all have a synergistic effect
.
Yimaitong: As early as 2005, China's National Medical Products Administration approved the first oncolytic adenovirus drug H101 (recombinant human adenovirus type 5, Encore®) combined with chemotherapy for the treatment of patients with advanced nasopharyngeal carcinoma
.
In the field of other solid tumors, H101 has also been explored and has shown good curative effects
.
Could you please briefly introduce the research progress and future application prospects of H101 in the field of solid tumors? Professor Wang Baocheng: H101 is the world's first and only oncolytic virus anti-tumor drug marketed in China
.
Early studies have shown that H101 monotherapy has a certain effect on malignant tumors, and it is well tolerated by patients
.
A number of studies have shown that H101 can bring clinical benefits to patients with tumors such as nasopharyngeal carcinoma, hepatocellular carcinoma, pancreatic cancer, and non-small cell lung cancer
.
A multi-center phase III clinical study in China compared the therapeutic effects and adverse reactions of intratumoral injection of H101 combined with chemotherapy and chemotherapy alone
.
The results showed that the complete remission (CR) rate and partial remission (PR) rate (CR+PR is effective) of H101 combined with chemotherapy were significantly higher than those of the chemotherapy group alone (72.
7% vs 40.
4%).
From the perspective of the systemic efficacy of the subjects, the combined The effective rate of the group was also significantly higher than that of the chemotherapy group alone (71.
2% vs 35.
1%)
.
In patients with advanced hepatocellular carcinoma, compared with TACE alone, H101 combined with TACE can significantly prolong the overall survival (OS) (12.
8 months vs 11.
6 months, P=0.
046) and progression-free survival (PFS) of the patients.
(10.
49 months vs 9.
72 months, P=0.
044), improve the CR rate of patients (14.
8% vs 28.
7%, P=0.
017) and reduce the disease progression (PD) rate (25.
0% vs 12.
6%, P=0.
011)
.
In addition, H101 can also be used as a single agent or in combination with recombinant human interleukin-2 to improve lung cancer malignant pleural and ascites, with effective rates reaching 69.
23% and 88.
9%, respectively
.
As an emerging tumor immunotherapy, oncolytic virus has been approved for use by regulatory agencies in China and many European and American countries
.
A large number of clinical studies have confirmed that the oncolytic virus therapy is clinically safe and can produce a relatively long-lasting response
.
Oncolytic viruses can be used not only in combination with immunotherapy, but also in combination with chemotherapy, radiotherapy, targeted therapy or surgery to maximize the potential of these therapies
.
Due to the complexity of the biology of oncolytic viruses, the diversity of cytokines and the arduousness of tumor treatment, the new era of tumor treatment is still in the dawn period
.
But there is no doubt that the oncolytic virus is full of light and opportunities ahead
.
With the continuous understanding of oncolytic viruses, we may be able to optimize them through genetic recombination, cytokine loading, cell vector packaging and other means in the future to make them play a greater role in killing tumors
.
I believe that with the progress of future research, researchers will develop more effective and safe oncolytic viruses, so that more cancer patients can benefit from it
.
.
In the long years of fighting the virus, people have developed a variety of drugs to fight against it, saving countless lives
.
Driven by coincidence and technological revolution, people discovered the possibility of "domesticating" the virus and using it for tumor treatment
.
Yimaitong invited Professor Wang Baocheng from the 960th Hospital of the People's Liberation Army to share with us the development history and mechanism of oncolytic viruses
.
Professor Wang Baocheng Chief Physician and Doctoral Tutor of the People’s Liberation Army 960 Hospital (formerly the General Hospital of Jinan Military Command), former Director of the Oncology Institute of Jinan Military Command, former Director of the Institute of Oncology of Jinan Military Command, Executive Director of the Chinese Society of Clinical Oncology (CSCO), CSCO Immunotherapy Committee Chairman, CSCO Anti- Oncology Drug Safety Management Expert Committee Standing Committee Member CSCO Liver Cancer Expert Committee Standing Committee CSCO Malignant Melanoma Expert Committee Standing Committee Member of the All Army Oncology Professional Committee Vice Chairman of the Central Military Commission Health Care Consultation Expert Vice Chairman of Shandong Medical Physician Association Director of the National Drug Clinical Verification Agency "China Digestion The editor-in-chief of the Journal of Diseases and Imaging, etc.
Yimaitong: In 2010, the FDA approved a series of immunotherapy drugs, opening a new era of tumor immunotherapy
.
Prior to this, tumor immunotherapy has gone through more than one hundred years of exploration.
Could you please introduce the development history of tumor immunotherapy? Professor Wang Baocheng: Tumor immunotherapy has experienced more than one hundred years of development.
It can be said that it has experienced ups and downs, and even stagnated for a while
.
However, in the past two to three decades, tumor immunotherapy has achieved rapid development and is expected to become an important weapon for curing tumors
.
Tumor immunotherapy can be roughly divided into the following stages: The first stage is the exploratory period
.
The discovery of Coley toxin represents the beginning of immunotherapy for malignant tumors
.
In 1866, German surgeon Wilhelm Busch discovered that after a patient with sarcoma was infected with erysipelas, the tumor subsided unexpectedly
.
Subsequently, New York surgeon Coley observed multiple cases of tumor regression after acute bacterial infections in tumor patients.
This discovery inspired Coley's lifelong clinical trials with bacterial filters
.
Coley uses a filtered mixture of dead Streptococcus pyogenes and Serratia marcescens to treat tumors.
This mixed vaccine is called "Coley toxin"
.
In a few patients, Coley was successful (20%)
.
However, due to the excessive toxicity of Coley toxin (mainly high fever), this treatment method has gradually faded out of people's sight
.
But Coley's contribution is a landmark, so it is also recorded in the annals of history
.
The second stage is the restructuring development period.
Immunotherapy focuses on the injection of restructured bacterial products or extracts, such as BCG and Corynebacterium parvum, into the tumor and in the body to enhance the body's non-specific immunity
.
The toxicity of this method is significantly reduced, but the curative effect is average
.
The third stage is the cytokine regulation period.
Researchers have discovered that gene recombination technology can promote the production of large amounts of cytokines in cells, which can be used for tumor treatment, such as recombinant IFN-α, IL-2, TNF, and so on
.
The fourth stage is the outbreak period
.
There are two important breakthroughs in this stage.
One is the discovery of immune checkpoints
.
American and Japanese scientists have successively discovered immune checkpoint molecules: cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1), It reveals the negative immune regulation mechanism, and promotes the wide application of current immune checkpoint inhibitors
.
Therefore, the main discoverers-Professor Allison from the United States and Professor Shusuke Moto from Japan won the 2018 Nobel Prize in Physiology or Medicine
.
Another breakthrough is the development of chimeric antigen receptor T cell technology (CAR-T) and other chimeric antigen receptor immune cell technology (CAR-NK, etc.
)
.
From the end of the 20th century to the present, the clinical applications of recombinant cytokines, monoclonal antibody technology, immune cell therapy, tumor vaccines, oncolytic viruses, immune checkpoint inhibitors, etc.
, have greatly improved the clinical benefits of tumor patients and made tumor immune The treatment has entered a stage of comprehensive development
.
Yimaitong: The human immune system is the key guarantee to protect the body from external diseases
.
Could you please introduce why tumor cells can evade immune surveillance, and how does immunotherapy identify "pretenders"? Professor Wang Baocheng: Tumor cells are very cunning and use various methods to evade recognition or attack by the body's immune system.
We call this "immune escape"
.
The body's anti-tumor immune response roughly consists of 7 stages: antigen release from necrotic tumor cells, antigen capture, processing and presentation, antigen recognition and T cell activation, T cell proliferation and migration, immune cell infiltration, re-recognition and tumor killing and so on
.
Any link of these 7 steps will cause tumor immune escape.
For example, tumors can not be recognized by immune cells through the lack or change of specific antigens; tumor cells can significantly reduce the number of immune cells around the tumor by preventing the infiltration of immune cells.
The formation of a local immune "desert"; tumor cells can also up-regulate the expression of immune checkpoint molecules, such as PD-1 and PD-L1, which severely inhibit T cell function and make T cells lose their ability to kill tumors, etc.
.
A sound immune system regulates immune cells in a balanced state of activation and suppression.
If too strong, immune cells will attack their own tissues and produce autoimmune diseases, while too weak will lead to tumors
.
When a person's body is detected with tumor cells or even tumor masses, it means that the tumor cells have escaped the surveillance of the immune system
.
At this time, the body needs to restart the immune system to control malignant tumors
.
The basic principle of the effectiveness of immunotherapy against tumors is: Since the patient's body's immune checkpoints are overexpressed, immunosuppression is formed, as if a car was stepped on the brake
.
Then the injection of the immune checkpoint inhibitor will combine the inhibitor with the immune checkpoint, thereby removing the inhibitory factors, just like releasing the brakes of a car
.
Currently, the most in-depth researched immune checkpoints are PD-1/PD-L1, CTLA-4, TIM-3, LAG-3 and TIGIT
.
In addition, tumor immunotherapies also include CAR-T, tumor vaccines, oncolytic viruses, etc.
These immunotherapies have gradually become research hotspots in recent years
.
Yimaitong: You just mentioned that oncolytic virus is also an important tumor immunotherapy.
It is reported that many research advances have been made
.
Could you please introduce us the main types, anti-tumor mechanisms and characteristics of oncolytic viruses? Professor Wang Baocheng: Oncolytic viruses are a type of natural or genetically modified viruses that can selectively infect tumor cells without infecting normal cells.
They replicate in a large amount and eventually lyse tumor cells.
At the same time, they will release a large amount of tumor antigens and improve Tumor microenvironment
.
At present, dozens of oncolytic virus drugs have been developed for tumor treatment, five of which are most commonly used: adenovirus, herpes simplex virus type I (HSV-1), reovirus, vaccinia virus and Newcastle disease virus
.
Among them, two oncolytic viruses have completed phase III clinical studies as drugs and have been approved for marketing, namely H101 (recombinant human adenovirus type 5, Encore®) and T-VEC (HSV-1)
.
At present, it is believed that oncolytic viruses mainly exert anti-tumor activity through four mechanisms of action: the first is oncolytic effect.
Oncolytic viruses can replicate in tumor cells specifically and in a large amount, which is mainly due to the specificity of tumors.
Aberrations cause cell signal transduction pathways to fail to recognize and block virus replication.
At the same time, tumor cells are defective in interferon production and cannot regulate the virus defense system, resulting in the final lysis of tumor cells
.
The second is that after tumor cells are lysed, a large amount of antigens are released, which stimulates an anti-tumor immune response, and by inducing chemotaxis, it turns "cold" tumors into "hot" tumors
.
The third is anti-angiogenesis.
Oncolytic viruses can infect and destroy tumor vasculature, induce neutrophil influx, and cause vascular collapse and tumor cell death
.
The fourth is to further enhance the oncolysis effect through the modification of viruses and virus-carrying genes
.
Most oncolytic viruses used in clinical trials have undergone genetic modification, and GM-CSF is the most commonly used inserted gene
.
Compared with traditional immunotherapy, oncolytic virus drugs have good targeting, less side effects, and multiple anti-tumor pathways (such as oncolytic effect, anti-angiogenesis, stimulating anti-tumor immune response, enhanced oncolysis through genetic modification), and difficult It produces advantages such as drug resistance
.
In addition, the combination of oncolytic virus drugs and chemotherapy, radiotherapy, and immunotherapy all have a synergistic effect
.
Yimaitong: As early as 2005, China's National Medical Products Administration approved the first oncolytic adenovirus drug H101 (recombinant human adenovirus type 5, Encore®) combined with chemotherapy for the treatment of patients with advanced nasopharyngeal carcinoma
.
In the field of other solid tumors, H101 has also been explored and has shown good curative effects
.
Could you please briefly introduce the research progress and future application prospects of H101 in the field of solid tumors? Professor Wang Baocheng: H101 is the world's first and only oncolytic virus anti-tumor drug marketed in China
.
Early studies have shown that H101 monotherapy has a certain effect on malignant tumors, and it is well tolerated by patients
.
A number of studies have shown that H101 can bring clinical benefits to patients with tumors such as nasopharyngeal carcinoma, hepatocellular carcinoma, pancreatic cancer, and non-small cell lung cancer
.
A multi-center phase III clinical study in China compared the therapeutic effects and adverse reactions of intratumoral injection of H101 combined with chemotherapy and chemotherapy alone
.
The results showed that the complete remission (CR) rate and partial remission (PR) rate (CR+PR is effective) of H101 combined with chemotherapy were significantly higher than those of the chemotherapy group alone (72.
7% vs 40.
4%).
From the perspective of the systemic efficacy of the subjects, the combined The effective rate of the group was also significantly higher than that of the chemotherapy group alone (71.
2% vs 35.
1%)
.
In patients with advanced hepatocellular carcinoma, compared with TACE alone, H101 combined with TACE can significantly prolong the overall survival (OS) (12.
8 months vs 11.
6 months, P=0.
046) and progression-free survival (PFS) of the patients.
(10.
49 months vs 9.
72 months, P=0.
044), improve the CR rate of patients (14.
8% vs 28.
7%, P=0.
017) and reduce the disease progression (PD) rate (25.
0% vs 12.
6%, P=0.
011)
.
In addition, H101 can also be used as a single agent or in combination with recombinant human interleukin-2 to improve lung cancer malignant pleural and ascites, with effective rates reaching 69.
23% and 88.
9%, respectively
.
As an emerging tumor immunotherapy, oncolytic virus has been approved for use by regulatory agencies in China and many European and American countries
.
A large number of clinical studies have confirmed that the oncolytic virus therapy is clinically safe and can produce a relatively long-lasting response
.
Oncolytic viruses can be used not only in combination with immunotherapy, but also in combination with chemotherapy, radiotherapy, targeted therapy or surgery to maximize the potential of these therapies
.
Due to the complexity of the biology of oncolytic viruses, the diversity of cytokines and the arduousness of tumor treatment, the new era of tumor treatment is still in the dawn period
.
But there is no doubt that the oncolytic virus is full of light and opportunities ahead
.
With the continuous understanding of oncolytic viruses, we may be able to optimize them through genetic recombination, cytokine loading, cell vector packaging and other means in the future to make them play a greater role in killing tumors
.
I believe that with the progress of future research, researchers will develop more effective and safe oncolytic viruses, so that more cancer patients can benefit from it
.
