-
Categories
-
Pharmaceutical Intermediates
-
Active Pharmaceutical Ingredients
-
Food Additives
- Industrial Coatings
- Agrochemicals
- Dyes and Pigments
- Surfactant
- Flavors and Fragrances
- Chemical Reagents
- Catalyst and Auxiliary
- Natural Products
- Inorganic Chemistry
-
Organic Chemistry
-
Biochemical Engineering
- Analytical Chemistry
-
Cosmetic Ingredient
- Water Treatment Chemical
-
Pharmaceutical Intermediates
Promotion
ECHEMI Mall
Wholesale
Weekly Price
Exhibition
News
-
Trade Service
January 1, 2022/MedClub News/--In the field of tumor therapy, macrophages can not only inhibit tumor growth and progression, but also promote tumor cell growth, survival and angiogenesis through an immunosuppressive microenvironment
.
In the past decade, more and more tumor treatment strategies have focused on reversing the immunosuppressive state of the tumor microenvironment, reprogramming to restore the tumor microenvironment to normal, and further activating the anti-tumor function of immune cells
.
Recently, Zhang Jin’s research group at Zhejiang University School of Medicine and Mu Haibo, director of the Department of Oncology, Shulan (Hangzhou) Hospital, conducted a comprehensive review of the development of macrophage-based tumor drugs and immunotherapy, and checked the existing giants.
The development strategy of phagocytic tumor immunotherapy provides a comprehensive analysis and insights for researchers in this field
.
➤ The important role of macrophages in tumor immunity Macrophages are the key effector cells of innate immunity.
They are widely distributed in all tissues.
Their main functions are phagocytosis and antigen presentation
.
Macrophages are highly plastic and exhibit obvious functional differences in different microenvironments
.
Macrophages mainly have two polarization states, which are the pro-inflammatory M1 phenotype and the anti-inflammatory and pro-repair M2 phenotype
.
Compared with T cells, macrophages do not require complex antigen recognition mechanisms and can directly engulf and eliminate abnormal cells
.
In addition, macrophages are the main immune cell population in solid tumors, which can account for 50% of the main immune cell population, compared with T cell infiltration usually less than 10%
.
The macrophages recruited into the tumor microenvironment are transformed into tumor-associated macrophages (TAM) under certain conditions, and TAMs are generally M2 type, not only lacking the function of phagocytosis of tumor cells, but also in the occurrence of tumors It plays a very important role in the development, invasion and metastasis, immune evasion and its vascular and lymphangiogenesis, and leads to poor prognosis of many tumors
.
Therefore, how to find more immunosuppressive signals and revert M2 tumor-associated macrophages to M1 macrophages is very important for reversing the tumor immunosuppressive state
.
➤ Targeting TAMs to improve anti-tumor immune response Since the FDA approved the CTLA-4 antibody ipilimumab to treat metastatic melanoma in 2011, immune checkpoint inhibitors (ICIs) have significantly improved the prognosis of patients with metastatic and refractory cancer
.
So far, PD-1/L1 antibody therapy has shown efficacy in more than 15 cancer treatments, and the survival rate of melanoma and advanced non-small cell lung cancer has increased by more than three times
.
However, the effective rate of PD-1 antibody in most patients with advanced tumors is only 20%, and drug resistance is prone to appear during treatment
.
Through innate immune cell therapy, the development of effective phagocyte targets and the search for new innate immune checkpoints are important strategies to improve the response rate of tumor immunotherapy
.
In addition to the use of immune checkpoint mechanisms, strategies such as targeting antibodies and regulating cell metabolism to reverse TAMs can also be used to improve the phagocytic capacity of macrophages
.
In addition, macrophage therapy can be developed through gene editing technology to reverse the immunosuppressive state
.
In vitro infusion of engineered macrophages activates the tumor microenvironment, activates the activity of T cells in the body, and ultimately regulates the immunosuppressive state
.
How to make the macrophages infused into the patient's body become resistant to the tumor microenvironment in the body and continue to maintain the anti-tumor state is the focus that needs to be explored for the development of macrophage immunotherapy
.
▲ The principle of tumor immunotherapy based on macrophages
.
➤ Targeting macrophages to phagocytize checkpoints Macrophages have a variety of immunosuppressive receptors, which initiate inhibitory phagocytic signals after binding to ligands on the surface of tumor cells
.
The successful application of CD47 or PD1 antibodies reminds us that, in response to different tumor suppressor signals, exploring more immunosuppressive receptors in macrophages is essential for reversing the immunosuppressive state of the solid tumor microenvironment
.
At present, there are more than 30 inhibitory receptors in immune cells such as macrophages, which can be divided into two types according to their structural characteristics
.
One class belongs to the immunoglobulin superfamily (IgSF) of type I transmembrane proteins.
Most of the genes are located at 19q13, and most of them contain immunoreceptor tyrosine inhibitory motifs (ITIM)
.
These receptors mainly include FcγRII, signal regulatory protein α (SIRPα), paired immunoglobulin-like receptor (PIR), killer receptor (KIR), CD22 and PD-1
.
The other is the c-type lectin superfamily (CLSF) coding gene, located at 12p13, which belongs to the type II transmembrane protein
.
Mainly include Ly49 family, NKG2 family, CD94, CD72 and dendritic cell immune receptor (DCIR)
.
Inhibitory receptors and their respective ligands have been shown to play a role in the regulation of various cell activities, including NK cell response, macrophage-mediated phagocytosis (SIRPα-CD47), and T cell response (CTLA4-CD80/ CD86, PD-1-PD- L1 / 2) and the like
.
▲ Product of phagocytic checkpoint inhibitors entering clinical trials ➤ Macrophage therapy-genetically engineered macrophages reported in 1990 to use monocyte-derived macrophages as effector cells for adoptive immunotherapy for cancer patients The results of the Phase I clinical trial showed that macrophages were well tolerated in vivo with mild side effects1
.
However, early experiments failed to transport macrophages to the tumor site or the macrophages used lacked plasticity, resulting in rapid loss of anti-tumor phenotype
.
Due to the high density of collagen in the tumor microenvironment and the immunosuppressive state of "cold tumor" in solid tumor tissue, it will change the cell phenotype and affect the phagocytosis of macrophages
.
After macrophages survive for a period of time around the tumor microenvironment, they will passively transform into a non-phagocytic state with high expression of SIRPα
.
Some genetic engineering methods reduce the expression of SIRPα on the cell surface to enhance the phagocytosis of macrophages2
.
Therefore, how to control the plasticity of macrophages in vivo is the key to establishing adoptive transplantation of engineered macrophages
.
Another promising strategy for modifying macrophages is to construct macrophages expressing chimeric antigen receptors (CAR-MAC), which may be more effective than CAR-T in the treatment of solid tumors in certain specific scenarios
.
Chimeric antigen receptors target specific antigens, allowing macrophages to produce antigen-dependent phagocytosis3,4
.
Recently, research has developed a genetically engineered macrophage 3 that induces the differentiation of patient's autologous monocytes into macrophages and expresses the HER2 chimeric antigen receptor, which has antigen-specific phagocytosis in vitro , And can activate T cells through antigen presentation, which can significantly reduce tumor burden and prolong overall survival in solid tumor mouse models
.
However, the challenges for the development of genetically engineered macrophages based on patients’ autologous primary cells include: limited number of primary cells, limited transfection efficiency, and high individual heterogeneity may lead to differences in the functions of genetically engineered cells
.
In addition, immortalized primary immune cell lines are not suitable for clinical use
.
CAR-modified human induced pluripotent stem cells (iPSC) can provide a universal source of macrophages with antigen-specific phagocytosis, which can be mass-produced as a standardized cell product
.
Previous research reports have proved that this iPSC-derived CAR macrophages or CAR-iMAC can effectively kill tumor cells in an antigen-dependent manner, and inhibit the occurrence and development of tumors in tumor mouse models 4
.
Summary Macrophages, as natural immune cells, have the ability to phagocytose tumor cells, and can effectively achieve antigen presentation, activate T cells to exert cytotoxic effects to activate the immune system
.
Restoring the anti-tumor function of macrophages is more meaningful than simply eliminating macrophages to inhibit tumor growth
.
At the same time, tumor cells tend to inhibit the function of macrophages by expressing a variety of immunomodulatory molecules
.
Therefore, the discovery and application of macrophage immune checkpoints is essential to reshape the function of macrophages
.
At present, a variety of inhibitors that block immune checkpoint signaling pathways have been used in clinical treatment
.
In addition to the current macrophage-based immunotherapy, another strategy that uses immune cells combined with immune checkpoint therapy may effectively improve the anti-tumor effect
.
For example, compared to using CAR-M alone or using anti-PD-1 antibodies alone, the combination of CAR-M and immune checkpoint inhibitors may significantly enhance the anti-tumor effect
.
Therefore, in addition to TAMs-based immunotherapy methods that repolarize TAMs to M1-like phenotypes, we should also pay attention to macrophage-based cell therapy.
Genetically engineered macrophages can improve macrophage Phagocytosis and other regulatory functions significantly activate the tumor immune microenvironment
.
Exploring the way to reverse TAM and genetically engineered macrophages in the treatment of clinical curative effect is long and difficult
.
The study of immune checkpoint signaling pathways for different types of tumors and the in-depth exploration of the drug synergy between adoptive cell transplantation therapy and phagocytic checkpoint inhibitors will open up new ways for the development of effective tumor treatment combinations
.
In addition, the engineered macrophage technology derived from stem cells gives macrophages a stronger ability to target phagocytosis and regulate the tumor microenvironment.
The realization of universal cell product preparation is the key to the clinical application of macrophages
.
Regulating macrophages may bring us closer to achieving the original goal of curing cancer, without stopping, and reaching farther
.
Year-end inventory of selected recent articles: The development trends of gene editing in 2021Yimai’s new observation track inventoryThe "rising rookie" in delivery vehicles, domestic and foreign companies in the field of exosomes in recent years inventory of another company entering the game , CAR-macrophages add another boost to tumor immunotherapyYimai Meng broke the news that Tasly has introduced a new generation of ADC with a large amount of nearly 400 million U.
S.
dollars! The target FRα gradually emerges.
Yimai Meng broke the news that China’s first TCR-T therapy for cervical cancer was officially launched.
Yimai Meng broke the news to create a "smarter" CAR-NK.
Lu Guanda’s star company announced the listing Yimai Meng broke the news
.
In the past decade, more and more tumor treatment strategies have focused on reversing the immunosuppressive state of the tumor microenvironment, reprogramming to restore the tumor microenvironment to normal, and further activating the anti-tumor function of immune cells
.
Recently, Zhang Jin’s research group at Zhejiang University School of Medicine and Mu Haibo, director of the Department of Oncology, Shulan (Hangzhou) Hospital, conducted a comprehensive review of the development of macrophage-based tumor drugs and immunotherapy, and checked the existing giants.
The development strategy of phagocytic tumor immunotherapy provides a comprehensive analysis and insights for researchers in this field
.
➤ The important role of macrophages in tumor immunity Macrophages are the key effector cells of innate immunity.
They are widely distributed in all tissues.
Their main functions are phagocytosis and antigen presentation
.
Macrophages are highly plastic and exhibit obvious functional differences in different microenvironments
.
Macrophages mainly have two polarization states, which are the pro-inflammatory M1 phenotype and the anti-inflammatory and pro-repair M2 phenotype
.
Compared with T cells, macrophages do not require complex antigen recognition mechanisms and can directly engulf and eliminate abnormal cells
.
In addition, macrophages are the main immune cell population in solid tumors, which can account for 50% of the main immune cell population, compared with T cell infiltration usually less than 10%
.
The macrophages recruited into the tumor microenvironment are transformed into tumor-associated macrophages (TAM) under certain conditions, and TAMs are generally M2 type, not only lacking the function of phagocytosis of tumor cells, but also in the occurrence of tumors It plays a very important role in the development, invasion and metastasis, immune evasion and its vascular and lymphangiogenesis, and leads to poor prognosis of many tumors
.
Therefore, how to find more immunosuppressive signals and revert M2 tumor-associated macrophages to M1 macrophages is very important for reversing the tumor immunosuppressive state
.
➤ Targeting TAMs to improve anti-tumor immune response Since the FDA approved the CTLA-4 antibody ipilimumab to treat metastatic melanoma in 2011, immune checkpoint inhibitors (ICIs) have significantly improved the prognosis of patients with metastatic and refractory cancer
.
So far, PD-1/L1 antibody therapy has shown efficacy in more than 15 cancer treatments, and the survival rate of melanoma and advanced non-small cell lung cancer has increased by more than three times
.
However, the effective rate of PD-1 antibody in most patients with advanced tumors is only 20%, and drug resistance is prone to appear during treatment
.
Through innate immune cell therapy, the development of effective phagocyte targets and the search for new innate immune checkpoints are important strategies to improve the response rate of tumor immunotherapy
.
In addition to the use of immune checkpoint mechanisms, strategies such as targeting antibodies and regulating cell metabolism to reverse TAMs can also be used to improve the phagocytic capacity of macrophages
.
In addition, macrophage therapy can be developed through gene editing technology to reverse the immunosuppressive state
.
In vitro infusion of engineered macrophages activates the tumor microenvironment, activates the activity of T cells in the body, and ultimately regulates the immunosuppressive state
.
How to make the macrophages infused into the patient's body become resistant to the tumor microenvironment in the body and continue to maintain the anti-tumor state is the focus that needs to be explored for the development of macrophage immunotherapy
.
▲ The principle of tumor immunotherapy based on macrophages
.
➤ Targeting macrophages to phagocytize checkpoints Macrophages have a variety of immunosuppressive receptors, which initiate inhibitory phagocytic signals after binding to ligands on the surface of tumor cells
.
The successful application of CD47 or PD1 antibodies reminds us that, in response to different tumor suppressor signals, exploring more immunosuppressive receptors in macrophages is essential for reversing the immunosuppressive state of the solid tumor microenvironment
.
At present, there are more than 30 inhibitory receptors in immune cells such as macrophages, which can be divided into two types according to their structural characteristics
.
One class belongs to the immunoglobulin superfamily (IgSF) of type I transmembrane proteins.
Most of the genes are located at 19q13, and most of them contain immunoreceptor tyrosine inhibitory motifs (ITIM)
.
These receptors mainly include FcγRII, signal regulatory protein α (SIRPα), paired immunoglobulin-like receptor (PIR), killer receptor (KIR), CD22 and PD-1
.
The other is the c-type lectin superfamily (CLSF) coding gene, located at 12p13, which belongs to the type II transmembrane protein
.
Mainly include Ly49 family, NKG2 family, CD94, CD72 and dendritic cell immune receptor (DCIR)
.
Inhibitory receptors and their respective ligands have been shown to play a role in the regulation of various cell activities, including NK cell response, macrophage-mediated phagocytosis (SIRPα-CD47), and T cell response (CTLA4-CD80/ CD86, PD-1-PD- L1 / 2) and the like
.
▲ Product of phagocytic checkpoint inhibitors entering clinical trials ➤ Macrophage therapy-genetically engineered macrophages reported in 1990 to use monocyte-derived macrophages as effector cells for adoptive immunotherapy for cancer patients The results of the Phase I clinical trial showed that macrophages were well tolerated in vivo with mild side effects1
.
However, early experiments failed to transport macrophages to the tumor site or the macrophages used lacked plasticity, resulting in rapid loss of anti-tumor phenotype
.
Due to the high density of collagen in the tumor microenvironment and the immunosuppressive state of "cold tumor" in solid tumor tissue, it will change the cell phenotype and affect the phagocytosis of macrophages
.
After macrophages survive for a period of time around the tumor microenvironment, they will passively transform into a non-phagocytic state with high expression of SIRPα
.
Some genetic engineering methods reduce the expression of SIRPα on the cell surface to enhance the phagocytosis of macrophages2
.
Therefore, how to control the plasticity of macrophages in vivo is the key to establishing adoptive transplantation of engineered macrophages
.
Another promising strategy for modifying macrophages is to construct macrophages expressing chimeric antigen receptors (CAR-MAC), which may be more effective than CAR-T in the treatment of solid tumors in certain specific scenarios
.
Chimeric antigen receptors target specific antigens, allowing macrophages to produce antigen-dependent phagocytosis3,4
.
Recently, research has developed a genetically engineered macrophage 3 that induces the differentiation of patient's autologous monocytes into macrophages and expresses the HER2 chimeric antigen receptor, which has antigen-specific phagocytosis in vitro , And can activate T cells through antigen presentation, which can significantly reduce tumor burden and prolong overall survival in solid tumor mouse models
.
However, the challenges for the development of genetically engineered macrophages based on patients’ autologous primary cells include: limited number of primary cells, limited transfection efficiency, and high individual heterogeneity may lead to differences in the functions of genetically engineered cells
.
In addition, immortalized primary immune cell lines are not suitable for clinical use
.
CAR-modified human induced pluripotent stem cells (iPSC) can provide a universal source of macrophages with antigen-specific phagocytosis, which can be mass-produced as a standardized cell product
.
Previous research reports have proved that this iPSC-derived CAR macrophages or CAR-iMAC can effectively kill tumor cells in an antigen-dependent manner, and inhibit the occurrence and development of tumors in tumor mouse models 4
.
Summary Macrophages, as natural immune cells, have the ability to phagocytose tumor cells, and can effectively achieve antigen presentation, activate T cells to exert cytotoxic effects to activate the immune system
.
Restoring the anti-tumor function of macrophages is more meaningful than simply eliminating macrophages to inhibit tumor growth
.
At the same time, tumor cells tend to inhibit the function of macrophages by expressing a variety of immunomodulatory molecules
.
Therefore, the discovery and application of macrophage immune checkpoints is essential to reshape the function of macrophages
.
At present, a variety of inhibitors that block immune checkpoint signaling pathways have been used in clinical treatment
.
In addition to the current macrophage-based immunotherapy, another strategy that uses immune cells combined with immune checkpoint therapy may effectively improve the anti-tumor effect
.
For example, compared to using CAR-M alone or using anti-PD-1 antibodies alone, the combination of CAR-M and immune checkpoint inhibitors may significantly enhance the anti-tumor effect
.
Therefore, in addition to TAMs-based immunotherapy methods that repolarize TAMs to M1-like phenotypes, we should also pay attention to macrophage-based cell therapy.
Genetically engineered macrophages can improve macrophage Phagocytosis and other regulatory functions significantly activate the tumor immune microenvironment
.
Exploring the way to reverse TAM and genetically engineered macrophages in the treatment of clinical curative effect is long and difficult
.
The study of immune checkpoint signaling pathways for different types of tumors and the in-depth exploration of the drug synergy between adoptive cell transplantation therapy and phagocytic checkpoint inhibitors will open up new ways for the development of effective tumor treatment combinations
.
In addition, the engineered macrophage technology derived from stem cells gives macrophages a stronger ability to target phagocytosis and regulate the tumor microenvironment.
The realization of universal cell product preparation is the key to the clinical application of macrophages
.
Regulating macrophages may bring us closer to achieving the original goal of curing cancer, without stopping, and reaching farther
.
Year-end inventory of selected recent articles: The development trends of gene editing in 2021Yimai’s new observation track inventoryThe "rising rookie" in delivery vehicles, domestic and foreign companies in the field of exosomes in recent years inventory of another company entering the game , CAR-macrophages add another boost to tumor immunotherapyYimai Meng broke the news that Tasly has introduced a new generation of ADC with a large amount of nearly 400 million U.
S.
dollars! The target FRα gradually emerges.
Yimai Meng broke the news that China’s first TCR-T therapy for cervical cancer was officially launched.
Yimai Meng broke the news to create a "smarter" CAR-NK.
Lu Guanda’s star company announced the listing Yimai Meng broke the news
