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PD-1/PD-L1 immune checkpoint inhibitors provide additional treatment options for many lung cancers with negative driver genes, instead of only choosing chemotherapy with large side effects.
Through immunotherapy, many patients benefit and survive for a long time.
Unfortunately, immune checkpoint inhibitors will gradually become resistant, and the mechanism of resistance is often very complicated.
To solve the problem of tumor resistance, we must first understand the specific drug resistance mechanism, and then we can cover the water.
A review just published in the "Lung Cancer" magazine reported on the drug resistance mechanism of lung cancer immunotherapy.
The degree of cancer is the first time for everyone to make a corresponding interpretation: How do cancer cells sly bypass immunotherapy? How do we respond to it? Drug resistance: a difficult problem in immunotherapy.
For immunotherapy to work, some requirements are indispensable: high expression of PD-L1 in tumor cells, high tumor mutation burden TMB, and so on.
Most lung cancers still meet these requirements, so in recent years immunotherapy has gradually become the mainstay of lung cancer treatment.
If the tumor cell PD-L1 is highly expressed (≥50%), then one-third of patients will survive for more than five years after first-line treatment with pembrolizumab.
Because PD-1/PD-L1 monotherapy is sometimes not effective, one of the solutions is to combine them with other therapies, such as chemotherapy and CTLA-4 inhibitors.
Such a program prolongs the benefit period for patients, but unfortunately most patients will eventually resist resistance.
Resistance can be divided into two forms: Primary resistance: There is little response to immunotherapy from the beginning.
· Acquired drug resistance: The initial response to immunotherapy, but the tumor recurs after a period of time.
Judging from the current treatment data, it is possible to benefit from immunotherapy for a long time, and the proportion of patients who are not resistant to drug resistance is very small.
Is this no way? Not really! Why are tumors resistant to immunotherapy? To solve the problem of drug resistance in immunotherapy, it is necessary to thoroughly understand the drug resistance mechanism of tumors and to know oneself and the enemy.
These reasons may be inherent to the tumor or external to the tumor.
· Internal reasons for drug resistance: tumor cells are very cunning and will bypass immunotherapy through many mechanisms, such as affecting neoantigen expression, antigen presentation, and affecting immune co-suppressive signals.
How do tumor cells develop such abominable "superpowers"? They do it through gene mutation or abnormal gene expression.
It is possible to have this resistance at the beginning, or it may be gradually acquired over time.
· External causes of drug resistance: This involves the microenvironment of the tumor lesion and the patient's immune status.
These will affect the recognition and killing of tumor cells by our immune cells.
Especially in the tumor microenvironment, there are many types of immune cells, some of which can help kill the tumor, but there are some unstable cells that "turn in" the tumor and help the tumor avoid the attack of killer cells.
See tricks and dismantle tricks: potential strategies to overcome immunotherapy resistance.
Our immune response is very finely regulated and involves many complex biological processes.
On the one hand, we must let the immune system respond to invading external microorganisms and abnormal cells in a timely and effective manner.
In response, on the other hand, it is necessary to avoid over-activation of the immune system, otherwise normal cells and tissues will suffer from over-reaction.
In theory, as long as the immune suppression signal is blocked or the immune stimulation signal is activated, an anti-tumor immune response can be achieved.
In addition, adjusting the intestinal flora or performing corresponding operations in the tumor microenvironment will change the infiltration of immune cells into tumor foci and promote the immune anti-tumor response.
Figure 1.
Strategies to enhance the efficacy of lung cancer immunotherapy.
As shown in the figure above, we can see the specific mechanisms of tumor resistance to immunotherapy: 1.
CTLA-4 and PD-1/PD-L1 inhibitors joint.
This is the well-known immunotherapy Gemini, and has proven the advantages of the combination of the two in the treatment of a variety of solid tumors.
In advanced PD-L1 positive non-small cell lung cancer, compared with first-line chemotherapy, immunotherapy Gemini can improve overall survival.
2.
Enhance the costimulatory signal.
Enhance the anti-tumor activity of T cells and NK cells through agonists, such as OX40, CD137, CD40, GITR and other signals.
This trick is currently in clinical trials.
3.
Regulate the tumor microenvironment.
There are different kinds of immune cells and other cells around the tumor.
There are complex interactions between them, which directly or indirectly determine the response of tumor lesions to immunotherapy.
4.
Adoptive Cell Transfer Therapy (ACT).
Isolation of immunocompetent cells from tumor patients, amplification and functional identification in vitro, and then infusion to the patient, so as to achieve the purpose of directly killing the tumor or stimulating the body's immune response to kill the tumor cells.
Adoptive immunotherapy has achieved a 60% effective and highly durable complete response in advanced melanoma.
Encouraging results have also been observed in breast cancer and several other tumors.
5.
CART, the chimeric antigen receptor.
It is better for hematological tumors, but the effect is not ideal for solid tumors such as lung cancer.
This may be because the complexity of the tumor microenvironment weakens the infiltration and activity of T cells, or it may be the lack of specific antigens.
6.
Personalized neoantigen vaccine.
The vaccine allows the host's immune system to recognize tumor antigens and play an anti-tumor effect.
The main risk of this therapy is that some antigen proteins are present in tumor cells and normal cells, which will cause accidental injury, so it is critical to choose the right antigen.
Next-generation sequencing technology is helpful to the development of vaccines, and clinical trials are currently underway.
7.
Regulate the intestinal flora. The composition of the gastrointestinal flora will affect the response to immunotherapy.
If broad-spectrum antibiotics are used before or during treatment, the immunotherapy effect of lung cancer patients is often not very good.
Intestinal microbial transplantation may help improve efficacy.
8.
Chemo assists.
When chemotherapy kills tumor cells, it releases corresponding antigens, which stimulates the immune system to respond.
In the past decade, several combinations of chemotherapy and immunotherapy have been tested.
Nowadays, many patients with negative expression of PD-L1 are treated with immunotherapy and chemotherapy, and the effect is also good.
However, recent studies have shown that chemotherapy sometimes restores resistance to immunotherapy, which of course needs further confirmation.
9.
Radiotherapy assists.
Radiation can induce cell damage, leading to the release of tumor antigens and an increase in antigen presentation.
Tumor cells killed by radiotherapy can stimulate macrophages and inflammatory cytokines, which can produce innate immune responses and promote the migration of T cells to tumor lesions.
In addition, radiotherapy-mediated pro-inflammatory signals may also have an impact on the regulation of the tumor microenvironment.
It also has an effect on areas that have not been radiotherapy.
Figure 2.
Novel immunotherapy clinical trials carried out in lung cancer and the results suggest that immunotherapy is an anti-tumor weapon, but it is far from achieving its maximum effect.
Our understanding of the complex immune system of the human body is not deep enough, but this also happens to show that there is still a lot of room for improvement in immunotherapy.
We can make immunotherapy more effective through a variety of mechanisms.
Finally, the cancer degree reminds everyone that immunotherapy has entered medical insurance and the price has been reduced.
Today, I will introduce some mechanisms to enhance the efficacy of immunotherapy, such as combined chemotherapy and radiotherapy, avoiding the use of antibiotics, etc.
You can pay more attention during the treatment to enhance the effect of immunotherapy.
Cancer degree bless all patients and friends, all can benefit from immunotherapy.
Download the Cancer Degree APP, join the immunotherapy exchange group, and exchange and learn together.
References Ilaria Attili, et al.
, Strategies to overcome resistance to immune checkpoint blockade in lung cancer, Lung Cancer 154 (2021) 151–160
Through immunotherapy, many patients benefit and survive for a long time.
Unfortunately, immune checkpoint inhibitors will gradually become resistant, and the mechanism of resistance is often very complicated.
To solve the problem of tumor resistance, we must first understand the specific drug resistance mechanism, and then we can cover the water.
A review just published in the "Lung Cancer" magazine reported on the drug resistance mechanism of lung cancer immunotherapy.
The degree of cancer is the first time for everyone to make a corresponding interpretation: How do cancer cells sly bypass immunotherapy? How do we respond to it? Drug resistance: a difficult problem in immunotherapy.
For immunotherapy to work, some requirements are indispensable: high expression of PD-L1 in tumor cells, high tumor mutation burden TMB, and so on.
Most lung cancers still meet these requirements, so in recent years immunotherapy has gradually become the mainstay of lung cancer treatment.
If the tumor cell PD-L1 is highly expressed (≥50%), then one-third of patients will survive for more than five years after first-line treatment with pembrolizumab.
Because PD-1/PD-L1 monotherapy is sometimes not effective, one of the solutions is to combine them with other therapies, such as chemotherapy and CTLA-4 inhibitors.
Such a program prolongs the benefit period for patients, but unfortunately most patients will eventually resist resistance.
Resistance can be divided into two forms: Primary resistance: There is little response to immunotherapy from the beginning.
· Acquired drug resistance: The initial response to immunotherapy, but the tumor recurs after a period of time.
Judging from the current treatment data, it is possible to benefit from immunotherapy for a long time, and the proportion of patients who are not resistant to drug resistance is very small.
Is this no way? Not really! Why are tumors resistant to immunotherapy? To solve the problem of drug resistance in immunotherapy, it is necessary to thoroughly understand the drug resistance mechanism of tumors and to know oneself and the enemy.
These reasons may be inherent to the tumor or external to the tumor.
· Internal reasons for drug resistance: tumor cells are very cunning and will bypass immunotherapy through many mechanisms, such as affecting neoantigen expression, antigen presentation, and affecting immune co-suppressive signals.
How do tumor cells develop such abominable "superpowers"? They do it through gene mutation or abnormal gene expression.
It is possible to have this resistance at the beginning, or it may be gradually acquired over time.
· External causes of drug resistance: This involves the microenvironment of the tumor lesion and the patient's immune status.
These will affect the recognition and killing of tumor cells by our immune cells.
Especially in the tumor microenvironment, there are many types of immune cells, some of which can help kill the tumor, but there are some unstable cells that "turn in" the tumor and help the tumor avoid the attack of killer cells.
See tricks and dismantle tricks: potential strategies to overcome immunotherapy resistance.
Our immune response is very finely regulated and involves many complex biological processes.
On the one hand, we must let the immune system respond to invading external microorganisms and abnormal cells in a timely and effective manner.
In response, on the other hand, it is necessary to avoid over-activation of the immune system, otherwise normal cells and tissues will suffer from over-reaction.
In theory, as long as the immune suppression signal is blocked or the immune stimulation signal is activated, an anti-tumor immune response can be achieved.
In addition, adjusting the intestinal flora or performing corresponding operations in the tumor microenvironment will change the infiltration of immune cells into tumor foci and promote the immune anti-tumor response.
Figure 1.
Strategies to enhance the efficacy of lung cancer immunotherapy.
As shown in the figure above, we can see the specific mechanisms of tumor resistance to immunotherapy: 1.
CTLA-4 and PD-1/PD-L1 inhibitors joint.
This is the well-known immunotherapy Gemini, and has proven the advantages of the combination of the two in the treatment of a variety of solid tumors.
In advanced PD-L1 positive non-small cell lung cancer, compared with first-line chemotherapy, immunotherapy Gemini can improve overall survival.
2.
Enhance the costimulatory signal.
Enhance the anti-tumor activity of T cells and NK cells through agonists, such as OX40, CD137, CD40, GITR and other signals.
This trick is currently in clinical trials.
3.
Regulate the tumor microenvironment.
There are different kinds of immune cells and other cells around the tumor.
There are complex interactions between them, which directly or indirectly determine the response of tumor lesions to immunotherapy.
4.
Adoptive Cell Transfer Therapy (ACT).
Isolation of immunocompetent cells from tumor patients, amplification and functional identification in vitro, and then infusion to the patient, so as to achieve the purpose of directly killing the tumor or stimulating the body's immune response to kill the tumor cells.
Adoptive immunotherapy has achieved a 60% effective and highly durable complete response in advanced melanoma.
Encouraging results have also been observed in breast cancer and several other tumors.
5.
CART, the chimeric antigen receptor.
It is better for hematological tumors, but the effect is not ideal for solid tumors such as lung cancer.
This may be because the complexity of the tumor microenvironment weakens the infiltration and activity of T cells, or it may be the lack of specific antigens.
6.
Personalized neoantigen vaccine.
The vaccine allows the host's immune system to recognize tumor antigens and play an anti-tumor effect.
The main risk of this therapy is that some antigen proteins are present in tumor cells and normal cells, which will cause accidental injury, so it is critical to choose the right antigen.
Next-generation sequencing technology is helpful to the development of vaccines, and clinical trials are currently underway.
7.
Regulate the intestinal flora. The composition of the gastrointestinal flora will affect the response to immunotherapy.
If broad-spectrum antibiotics are used before or during treatment, the immunotherapy effect of lung cancer patients is often not very good.
Intestinal microbial transplantation may help improve efficacy.
8.
Chemo assists.
When chemotherapy kills tumor cells, it releases corresponding antigens, which stimulates the immune system to respond.
In the past decade, several combinations of chemotherapy and immunotherapy have been tested.
Nowadays, many patients with negative expression of PD-L1 are treated with immunotherapy and chemotherapy, and the effect is also good.
However, recent studies have shown that chemotherapy sometimes restores resistance to immunotherapy, which of course needs further confirmation.
9.
Radiotherapy assists.
Radiation can induce cell damage, leading to the release of tumor antigens and an increase in antigen presentation.
Tumor cells killed by radiotherapy can stimulate macrophages and inflammatory cytokines, which can produce innate immune responses and promote the migration of T cells to tumor lesions.
In addition, radiotherapy-mediated pro-inflammatory signals may also have an impact on the regulation of the tumor microenvironment.
It also has an effect on areas that have not been radiotherapy.
Figure 2.
Novel immunotherapy clinical trials carried out in lung cancer and the results suggest that immunotherapy is an anti-tumor weapon, but it is far from achieving its maximum effect.
Our understanding of the complex immune system of the human body is not deep enough, but this also happens to show that there is still a lot of room for improvement in immunotherapy.
We can make immunotherapy more effective through a variety of mechanisms.
Finally, the cancer degree reminds everyone that immunotherapy has entered medical insurance and the price has been reduced.
Today, I will introduce some mechanisms to enhance the efficacy of immunotherapy, such as combined chemotherapy and radiotherapy, avoiding the use of antibiotics, etc.
You can pay more attention during the treatment to enhance the effect of immunotherapy.
Cancer degree bless all patients and friends, all can benefit from immunotherapy.
Download the Cancer Degree APP, join the immunotherapy exchange group, and exchange and learn together.
References Ilaria Attili, et al.
, Strategies to overcome resistance to immune checkpoint blockade in lung cancer, Lung Cancer 154 (2021) 151–160
