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In recent years, with the continuous expansion of tumor treatment methods, studies have found that viruses have great potential in tumor treatment
.
With multiple anti-tumor mechanisms and advantages, oncolytic viruses have become a rising star in tumor immunotherapy
.
01 Understanding oncolytic viruses Oncolytic viruses (Ovs) are a type of natural or recombinant viruses that can selectively infect and kill cancer cells, but do not harm normal cells
.
So far, 4 OVs drugs have been approved worldwide (Table 1)
.
Table 1.
List of oncolytic viruses approved worldwide.
After recognizing that the true potential of viruses in cancer treatment lies in their ability to trigger a new type of cancer-specific acquired immune response against tumor antigens, oncolytic virus treatment has received more attention
.
These observations have turned the application of OVs from pure oncolytic drugs to anti-tumor immune activation drugs, and this field can now be more accurately referred to as "oncolytic immunotherapy
.
"
Another new direction of OVs is its potential application in cancer combination therapy, especially in combination with immune checkpoint inhibitors (ICIs) and T cell therapy
.
02 Types of oncolytic viruses An ideal oncolytic virus should have several characteristics: First, it must have a full understanding of its biology and genetics
.
OVs should be immunogenic, exert lytic activity in infected malignant cells, should not cause chronic or infectious diseases, or be able to integrate into the human genome
.
In addition, these viruses must be broadly safe for diverse populations
.
Currently OVs include DNA and RNA viruses (Table 2)
.
The oncolytic DNA virus has high genome stability and large transgene insertion ability without affecting virus infection and replication
.
On the other hand, RNA viruses have limited genome packaging capabilities, but some viruses are more immunogenic
.
Table 2.
List of Oncolytic Viruses Abbreviations: Herpes Simplex Virus (HSV), Vaccinia Virus (VACV), Myxoma Virus (MYXV), Measles Virus (MV), Newcastle Disease Virus (NDV), Seneca Valley Virus (SVV) , Semliki Forest Virus (SFV), Herpes Stomatitis Virus (VSV), Sindbis Virus (SBV) 03OVs' "tumorophilic" mechanism OVs usually depend on a variety of factors, such as virus binding/ Access (for some OVs, but not all OVs) necessary for cell surface receptors, cell metabolism, and the ability of viruses to overcome innate immunity or antiviral signaling pathways in cancer cells
.
Early observations were made that some OVs used unique extracellular molecules expressed on cancer cells to enter.
For example, CD46, CD155, and integrin α2β1 molecules are overexpressed in many types of tumor cells.
They can be used as measles virus, polio virus, and AIDS, respectively.
Ko virus receptor
.
It is worth noting that the same OV may use different cell surface receptors for different types of cancer
.
Cancer is a complex heterogeneous disease with multiple gene mutations that mediate changes in multiple antiviral signaling pathways, and these signaling pathways provide a perfect niche for the replication of OVs
.
Different OVs can take advantage of the selective defects of cancer cells.
Research in this field is still a hot spot and needs further exploration
.
Most tumor cell types are characterized by a high rate of aerobic glycolysis (Warburg effect), which plays a vital role in the development of the immunosuppressive tumor microenvironment (TME)
.
This is because tumor cells will cause excessive consumption of extracellular glucose, which in turn limits the availability of glucose to resident immune leukocytes, and ultimately reduces the proliferation and effector functions of immune cells (such as resident tumor T cells)
.
In addition, the accumulation of lactic acid in tissues caused by increased glycolysis in TME also severely affects the functional properties of local T cells and NK cells
.
Studies have shown that inhibiting glycolytic metabolism of tumor cells can enhance the anti-tumor immune response and the function of chemotherapeutic drugs
.
After infecting host cells, viruses also tend to activate glycolysis and enhance the synthesis of cell biomolecules and virus particles, thereby amplifying the Warburg effect
.
Exploring the multiple mechanisms by which viruses enhance glycolysis, as a strategy that is conducive to virus replication, many details still need to be fully studied
.
04OVs-mediated anti-tumor mechanism after binding and entering tumor cells, OVs can use a variety of lysis mechanisms to kill infected cancer cells.
The exact mechanism of viral oncolysis is not fully understood
.
OVs are thought to mediate anti-tumor activity through a variety of mechanisms: (a) selective replication of the virus in cancer cells, causing direct cytolysis (this mechanism is also called "oncolysis"); (b) cells The indirect effects of death (e.
g.
, apoptosis, necrosis) on infected and uninfected cancer cells and related endothelial cells in the tumor-associated vascular system, resulting in decreased angiogenesis; (c) activation of systemic anti-tumor (and anti-viral) immunity, The activated immune cells are recruited into the TME
.
However, these mechanisms vary greatly due to the nature and type of viruses, cancer cells, and the overall interaction between OVs, TME and the host immune system
.
In addition, in order to preferentially induce cell lysis, some OVs are designed to specifically activate different types of cancer cell death pathways, such as apoptosis, necrosis, autophagy or pyrolysis
.
05OVs monotherapy The efficacy of OV as a monotherapy is still limited.
Like many other modern cancer therapies, oncolytic virus therapy still faces challenges and obstacles in becoming a successful anti-cancer therapy
.
Some key factors can lead to functional limitations: (1) unknown host antiviral pathways restrict the activity and spread of OVs; (2) surrounding internal physical barriers restrict the spread of OVs on the tumor bed; (3) adaptive immune response indirect restriction The function of the virus
.
In addition, other factors should be considered: a.
Selection of the best OVs candidate virus; b.
Virus entry, infection and spread: The expression of these receptors is reduced or not expressed by the OVs that use selected cell surface receptors to bind and enter.
The tumor is usually useless; c.
Delivery of OVs: The delivery of OVs to the primary site and metastatic site is essential for the best treatment outcome
.
In this regard, since only a small number of human cancers can accept direct intratumoral injection (IT), systemic injection is the preferred route compared with IT injection of viruses; d.
Neutralizing antibodies and antiviral cytokines: when free virus reaches the tumor In the process of systemic delivery of the bed, pre-existing neutralizing antiviral antibodies are the main obstacle; e.
Immunosuppressive TME: Another obstacle to the treatment of OVs is the frequent occurrence of highly immunosuppressive TME
.
06OVs combined treatment of OVs has a multi-mechanism therapeutic effect on most types of cancer (Figure 1)
.
However, in clinical trials of monotherapy, OVs using an earlier generation (such as GM-CSF) showed complete remission in a relatively small number of patients
.
Although processing OVs through different methods can enhance oncolytic activity and activate anti-tumor immune responses, it has been reported that OVs are more effective when used in combination with other cancer treatments (such as chemotherapy, radiotherapy, immunotherapy or cell therapy)
.
Figure 1.
Therapeutic characteristics and improvement approaches of oncolytic virus therapy.
OVs combined with radiotherapy have been explored in preclinical models and some clinical trials
.
The combination of radiotherapy and OVs has a synergistic anti-tumor effect, especially for aggressive tumors where other treatment methods have failed
.
Different from intratumoral administration, the systemic administration of OVs faces many challenges, mainly due to the ability of the immune filtration system to detect and eliminate pathogens in the circulatory system
.
Many types of vector cells have been tested to determine whether they are suitable for systemic delivery of OVs to overcome the shortcomings of intravenous virus injection
.
Among the many vector cells tested so far, patient-derived mesenchymal stem cells (MSCs) have attracted attention and have been tested with OVs in clinical trials
.
In addition to MSCs, neural stem cells (NSCs) also improve the delivery of OV in a variety of cancer models
.
Another potential carrier cell is chimeric antigen receptor T (CAR-T) cells, which are designed to recognize and kill target cancer cells
.
OVs combined with immune checkpoint inhibitors (ICIs) also present many challenges
.
ICIs that target immune checkpoints such as PD-1, PD-L1 or CTLA-4 and destroy the ability of cancer cells to evade the host's immune response have become one of the key cancer treatments
.
However, ICIs still have limitations: (1) only a limited portion (10-20%) of patients respond to ICIs treatment; (2) immune-related adverse reactions have been reported in some patients receiving ICIs treatment; (3) Immune "cold" tumors characterized by low tumor infiltrating lymphocytes (TILs) have limited efficacy
.
Cellular immunotherapy, also known as "adoptive cell therapy", uses modified immune system cells to eliminate cancer cells
.
Various types of cellular immunotherapy has been developed: The CAR-T cell therapy, TIL therapy
.
Among these cell-based therapies, CAR-T cell therapy as an emerging immunotherapy has shown significant efficacy in hematological tumors
.
However, further research is needed in solid tumors
.
In order to overcome these limitations, cell therapy is being explored in conjunction with OVs in order to achieve synergy
.
Conclusion Over thirty years of extensive research and clinical trials have proved that OVs therapy is a promising cancer treatment
.
In terms of safety, efficacy, selectivity, administration methods and production, OVs therapy has been significantly improved, which further clarifies that OVs can be used as powerful cancer treatment candidates
.
However, it is becoming increasingly clear that OVs as a single-agent therapy may not provide a complete cancer treatment response.
Therefore, the exploration of combination strategies is the direction.
The rational design of combination programs to alleviate the limitations of OVs and other treatments for specific cancer types is still Is a challenge
.
References: 1.
OncolyticViruses: Newest Frontier for Cancer Immunotherapy.
Cancers (Basel).
2021Nov; 13(21): 5452.
.
With multiple anti-tumor mechanisms and advantages, oncolytic viruses have become a rising star in tumor immunotherapy
.
01 Understanding oncolytic viruses Oncolytic viruses (Ovs) are a type of natural or recombinant viruses that can selectively infect and kill cancer cells, but do not harm normal cells
.
So far, 4 OVs drugs have been approved worldwide (Table 1)
.
Table 1.
List of oncolytic viruses approved worldwide.
After recognizing that the true potential of viruses in cancer treatment lies in their ability to trigger a new type of cancer-specific acquired immune response against tumor antigens, oncolytic virus treatment has received more attention
.
These observations have turned the application of OVs from pure oncolytic drugs to anti-tumor immune activation drugs, and this field can now be more accurately referred to as "oncolytic immunotherapy
.
"
Another new direction of OVs is its potential application in cancer combination therapy, especially in combination with immune checkpoint inhibitors (ICIs) and T cell therapy
.
02 Types of oncolytic viruses An ideal oncolytic virus should have several characteristics: First, it must have a full understanding of its biology and genetics
.
OVs should be immunogenic, exert lytic activity in infected malignant cells, should not cause chronic or infectious diseases, or be able to integrate into the human genome
.
In addition, these viruses must be broadly safe for diverse populations
.
Currently OVs include DNA and RNA viruses (Table 2)
.
The oncolytic DNA virus has high genome stability and large transgene insertion ability without affecting virus infection and replication
.
On the other hand, RNA viruses have limited genome packaging capabilities, but some viruses are more immunogenic
.
Table 2.
List of Oncolytic Viruses Abbreviations: Herpes Simplex Virus (HSV), Vaccinia Virus (VACV), Myxoma Virus (MYXV), Measles Virus (MV), Newcastle Disease Virus (NDV), Seneca Valley Virus (SVV) , Semliki Forest Virus (SFV), Herpes Stomatitis Virus (VSV), Sindbis Virus (SBV) 03OVs' "tumorophilic" mechanism OVs usually depend on a variety of factors, such as virus binding/ Access (for some OVs, but not all OVs) necessary for cell surface receptors, cell metabolism, and the ability of viruses to overcome innate immunity or antiviral signaling pathways in cancer cells
.
Early observations were made that some OVs used unique extracellular molecules expressed on cancer cells to enter.
For example, CD46, CD155, and integrin α2β1 molecules are overexpressed in many types of tumor cells.
They can be used as measles virus, polio virus, and AIDS, respectively.
Ko virus receptor
.
It is worth noting that the same OV may use different cell surface receptors for different types of cancer
.
Cancer is a complex heterogeneous disease with multiple gene mutations that mediate changes in multiple antiviral signaling pathways, and these signaling pathways provide a perfect niche for the replication of OVs
.
Different OVs can take advantage of the selective defects of cancer cells.
Research in this field is still a hot spot and needs further exploration
.
Most tumor cell types are characterized by a high rate of aerobic glycolysis (Warburg effect), which plays a vital role in the development of the immunosuppressive tumor microenvironment (TME)
.
This is because tumor cells will cause excessive consumption of extracellular glucose, which in turn limits the availability of glucose to resident immune leukocytes, and ultimately reduces the proliferation and effector functions of immune cells (such as resident tumor T cells)
.
In addition, the accumulation of lactic acid in tissues caused by increased glycolysis in TME also severely affects the functional properties of local T cells and NK cells
.
Studies have shown that inhibiting glycolytic metabolism of tumor cells can enhance the anti-tumor immune response and the function of chemotherapeutic drugs
.
After infecting host cells, viruses also tend to activate glycolysis and enhance the synthesis of cell biomolecules and virus particles, thereby amplifying the Warburg effect
.
Exploring the multiple mechanisms by which viruses enhance glycolysis, as a strategy that is conducive to virus replication, many details still need to be fully studied
.
04OVs-mediated anti-tumor mechanism after binding and entering tumor cells, OVs can use a variety of lysis mechanisms to kill infected cancer cells.
The exact mechanism of viral oncolysis is not fully understood
.
OVs are thought to mediate anti-tumor activity through a variety of mechanisms: (a) selective replication of the virus in cancer cells, causing direct cytolysis (this mechanism is also called "oncolysis"); (b) cells The indirect effects of death (e.
g.
, apoptosis, necrosis) on infected and uninfected cancer cells and related endothelial cells in the tumor-associated vascular system, resulting in decreased angiogenesis; (c) activation of systemic anti-tumor (and anti-viral) immunity, The activated immune cells are recruited into the TME
.
However, these mechanisms vary greatly due to the nature and type of viruses, cancer cells, and the overall interaction between OVs, TME and the host immune system
.
In addition, in order to preferentially induce cell lysis, some OVs are designed to specifically activate different types of cancer cell death pathways, such as apoptosis, necrosis, autophagy or pyrolysis
.
05OVs monotherapy The efficacy of OV as a monotherapy is still limited.
Like many other modern cancer therapies, oncolytic virus therapy still faces challenges and obstacles in becoming a successful anti-cancer therapy
.
Some key factors can lead to functional limitations: (1) unknown host antiviral pathways restrict the activity and spread of OVs; (2) surrounding internal physical barriers restrict the spread of OVs on the tumor bed; (3) adaptive immune response indirect restriction The function of the virus
.
In addition, other factors should be considered: a.
Selection of the best OVs candidate virus; b.
Virus entry, infection and spread: The expression of these receptors is reduced or not expressed by the OVs that use selected cell surface receptors to bind and enter.
The tumor is usually useless; c.
Delivery of OVs: The delivery of OVs to the primary site and metastatic site is essential for the best treatment outcome
.
In this regard, since only a small number of human cancers can accept direct intratumoral injection (IT), systemic injection is the preferred route compared with IT injection of viruses; d.
Neutralizing antibodies and antiviral cytokines: when free virus reaches the tumor In the process of systemic delivery of the bed, pre-existing neutralizing antiviral antibodies are the main obstacle; e.
Immunosuppressive TME: Another obstacle to the treatment of OVs is the frequent occurrence of highly immunosuppressive TME
.
06OVs combined treatment of OVs has a multi-mechanism therapeutic effect on most types of cancer (Figure 1)
.
However, in clinical trials of monotherapy, OVs using an earlier generation (such as GM-CSF) showed complete remission in a relatively small number of patients
.
Although processing OVs through different methods can enhance oncolytic activity and activate anti-tumor immune responses, it has been reported that OVs are more effective when used in combination with other cancer treatments (such as chemotherapy, radiotherapy, immunotherapy or cell therapy)
.
Figure 1.
Therapeutic characteristics and improvement approaches of oncolytic virus therapy.
OVs combined with radiotherapy have been explored in preclinical models and some clinical trials
.
The combination of radiotherapy and OVs has a synergistic anti-tumor effect, especially for aggressive tumors where other treatment methods have failed
.
Different from intratumoral administration, the systemic administration of OVs faces many challenges, mainly due to the ability of the immune filtration system to detect and eliminate pathogens in the circulatory system
.
Many types of vector cells have been tested to determine whether they are suitable for systemic delivery of OVs to overcome the shortcomings of intravenous virus injection
.
Among the many vector cells tested so far, patient-derived mesenchymal stem cells (MSCs) have attracted attention and have been tested with OVs in clinical trials
.
In addition to MSCs, neural stem cells (NSCs) also improve the delivery of OV in a variety of cancer models
.
Another potential carrier cell is chimeric antigen receptor T (CAR-T) cells, which are designed to recognize and kill target cancer cells
.
OVs combined with immune checkpoint inhibitors (ICIs) also present many challenges
.
ICIs that target immune checkpoints such as PD-1, PD-L1 or CTLA-4 and destroy the ability of cancer cells to evade the host's immune response have become one of the key cancer treatments
.
However, ICIs still have limitations: (1) only a limited portion (10-20%) of patients respond to ICIs treatment; (2) immune-related adverse reactions have been reported in some patients receiving ICIs treatment; (3) Immune "cold" tumors characterized by low tumor infiltrating lymphocytes (TILs) have limited efficacy
.
Cellular immunotherapy, also known as "adoptive cell therapy", uses modified immune system cells to eliminate cancer cells
.
Various types of cellular immunotherapy has been developed: The CAR-T cell therapy, TIL therapy
.
Among these cell-based therapies, CAR-T cell therapy as an emerging immunotherapy has shown significant efficacy in hematological tumors
.
However, further research is needed in solid tumors
.
In order to overcome these limitations, cell therapy is being explored in conjunction with OVs in order to achieve synergy
.
Conclusion Over thirty years of extensive research and clinical trials have proved that OVs therapy is a promising cancer treatment
.
In terms of safety, efficacy, selectivity, administration methods and production, OVs therapy has been significantly improved, which further clarifies that OVs can be used as powerful cancer treatment candidates
.
However, it is becoming increasingly clear that OVs as a single-agent therapy may not provide a complete cancer treatment response.
Therefore, the exploration of combination strategies is the direction.
The rational design of combination programs to alleviate the limitations of OVs and other treatments for specific cancer types is still Is a challenge
.
References: 1.
OncolyticViruses: Newest Frontier for Cancer Immunotherapy.
Cancers (Basel).
2021Nov; 13(21): 5452.
