Writer | Katherine Yang
Layout Designer | Cecilia Qin
IMMUNOTHERAPY
Cancer is also known as a malignant tumor. As the first of the top ten causes of death for human beings, it has always been a problem that has troubled us very much. Since the beginning of the development of medicine, human beings have been trying many ways to treat cancer. There are currently five major methods for cancer treatment: surgery, chemotherapy, radiation therapy, targeted drugs, and the latest immunotherapy. This article will focus on immunotherapy that drives human immune function, which can be subdivided into four primary methods: immune drugs, immune cell therapy, cancer vaccines, and bacterial therapy.
How do cancer cells avoid the search of immune cells?
As everyone knows, the occurrence of cancer is the continuous proliferation of cells caused by abnormal mutations in human genes, and it is extremely difficult for human immune cells to recognize cancer cells, which often leads to people finding it after seeking medical treatment due to discomfort. Normally, such abnormal cells should be discovered and killed by immune cells. However, cancer cells evade the search of immune cells by relying on his three tricks. Therefore, understanding the principle of cancer cell evasion is the key for humans to find corresponding treatment methods.
Trick 1: Pretend to be a transparent person
Almost all nucleated cells in vertebrates contain a very important protein—Major histocompatibility complex class I (MHC-I). MHC-I is the key for immune cells to distinguish between friend and enemy. When a cell is infected by a virus or becomes cancerous, it will present virus or tumor antigens through the MHC-I on the cell surface, allowing immune cells to kill the mutated cells. Cancer cells will reduce the concentration of their own MHC-I and turn themselves into "transparent people" to avoid the search of immune cells.
Trick 2: I am a good person
There is another protein on the surface of normal cells in the human body -- CD47. When CD47 binds to the signal regulatory protein α (SIRPα) on the surface of immune cells, it will display a "don't eat me" signal to immune cells. Normally, CD47 is only present on the surface of normal cells, but the researchers found that cancer cells also have CD47 on the surface. In other words, when immune cells encounter cancer cells, they think the cancer cells are good people.
Trick 3: Stop immune cells from attacking
In order to prevent immune cells from being crazy and causing a cytokine storm in patients, immune cells have some unique "brake mechanisms" called "immune checkpoints". There are currently three known T cell immune checkpoints, namely PD-1, CTLA-4, and LAG-3; and there are also special proteins on the surface of cancer cells that can bind to immune checkpoints, reducing the ability of T cells to attack.
The development of cancer treatment
Humans can't understand cancer overnight. Actually, it takes us thousands of years. According to historical records, as early as 3000 BC, doctors at that time had used surgical resection to treat cancer, but it was not until 1891 AD that new treatments appeared. In 1891, American physician William Curley first used bacteriotherapy, which uses bacteria to treat cancer in the human body. However, at that time, Dr. Curley could not explain the principle of the therapy, so he was widely opposed by the academic community. Through time came the 20th century, when radiation therapy, chemotherapy, and targeted therapy appeared one after another. And at the beginning of the 21st century, was the time when immunotherapy (immune drugs, cell therapy, etc.) flourished. However, as scientists have understood the principles of bacterial therapy in recent years, perhaps bacterial therapy will become another new trend.
Immunotherapy
In 2007, Nature magazine published a paper confirming the connection between cancer cells and the immune system. And the paper further pointed out that T cells have the highest correlation with the occurrence of cancer. Therefore, humans have started research on T cells and cancer treatment.
Immunological drugs
The full name of immune drugs is commonly known as immune checkpoint inhibitors, which subdue cancer cells by using the third trick mentioned above. Taking PD-1 on the surface of T cells as an example, PD-1 will bind to PD-L1 on the surface of cancer cells, resulting in a decrease in the attacking ability of T cells. Immunopharmaceuticals use drug molecules to preempt cancer cells and bind to PD-1; however, this combination does not lead to a decrease in the attacking ability of T cells and only avoids the possibility of combining PD-1 and PD-L1.
Immunopharmaceuticals can be applied to 17 types of cancer, including lung cancer, gastric cancer, esophageal cancer, head and neck cancer, cervical cancer, and hepatocellular carcinoma, with mild side effects, and the activation effect on the immune system can be preserved for 3 to 5 years after stopping the drug. However, with current technology, the success rate of this therapy is not high, and only 15% to 30% of solid tumor cancers respond to immune drugs.
Doctors currently use three indicators to judge whether a patient is suitable for immunotherapy, namely the expression of PD-L1, microsatellite instability (MSI), and tumor mutation load (TMB).
The expression of PD-L1
The higher the expression of PD-L1 on cancer cells, the higher the probability of effective immunotherapy. According to the latest ESMO Guidelines in 2019, when a patient's PD-L1 expression is ≥ 50%, immunotherapy is suitable for first-line treatment; if the patient's PD-L1 expression is < 50%, it is recommended to use Chemotherapy and immunological drugs together.
Microsatellite instability (MSI)
Microsatellites refer to DNA repeats in cancer cells. The higher a patient's MSI is, the more unstable his DNA is, making it easier for the immune system to identify abnormal cells.
Tumor mutation load (TMB)
The principle of TMB is similar to that of MSI. The more mutated a tumor is, the more likely it is to produce mutated proteins and trigger the body's immune response.
Immune cell therapy
At present, researchers have discovered two methods of immune cell therapy, CAR-T cell therapy invented in 2019, and TCR-T cell therapy invented at the end of 2022. Both of these cell therapies "strengthen" T cells in the body through gene editing. The following will introduce the two therapies separately.
CAR-T cell therapy
The secret weapon to strengthen T cells - CAR
CAR is the abbreviation of Chimeric Antigen Receptor. As the name suggests, CAR-T cell therapy is to add chimeric antigen receptors on the surface of T cells through gene editing.
The CAR can be regarded as a protein composed of three parts. The protein outside the T cell is an antibody molecule with high specificity and strong affinity for the surface antigen of the cancer cell; the middle block is responsible for maintaining the stability of the CAR so that it can maintain on the surface of T cells; and the block in T cells can be used to trigger intracellular signaling pathways. When a CAR antibody attached to the surface of a T cell comes into contact with a cancer cell, the CAR activates the T cell, causing it to kill the cancer cell. Therefore, in theory, as long as the antibody at the top of the CAR protein is replaced, various cancers can be attacked, which is also the biggest incentive for major pharmaceutical companies to develop one after another.
The limitations of CAR-T cell therapy
There are currently only six CAR-T cell preparations approved by the US Food and Drug Administration (FDA), all of which are used to treat blood and lymphoid cancers. Among them, CAR-T cells are most effective in the treatment of Acute B Lymphocytic Leukemia (ALL), with an effective rate of more than 90% for advanced patients. But CAR-T cell therapy is less effective for cancers with solid tumors, and there are three reasons. The first reason is the heterogeneity of solid tumors. From a microscopic perspective, each tumor is composed of many kinds of mutated cancer cells. That is to say, the location of the mutation in the cancer cells in the tumor is not the same. But CAR-T cell therapy is to find "commonly owned" antigens on the surface of cancer cells. So obviously, the heterogeneity of solid tumors has a great conflict with the fundamental principle of CAR-T cell therapy. If the mutations between cancer cells are different, the antigens presented on their surface will also be different. If CAR-T cells are administered, there will always be some cancer cells that are not killed, and these surviving cancer cells will multiply rapidly and occupy the position of the dead cancer cells. The second reason is that the blood vessels in the tumor cannot keep up with the proliferation of cancer cells, resulting in the tumor being always in a state of hypoxia. Even if the immune cells successfully enter the tumor, they will not be able to function due to hypoxia. Third, cancer cells secrete chemicals that suppress the activity of immune cells and also make immune cells unable to function. Of course, this is not completely insurmountable. Researchers are now trying to make more CAR on the surface of T cells, but the concept is still experimental.
However, in addition to being unable to overcome solid cancers, CAR-T cell therapy has another dilemma waiting for a breakthrough. Since the current technology uses the patient's own T cells, this allows CAR-T cells to be reinfused into the patient without rejection. However, this production method also makes CAR-T cell therapy an extremely personalized therapy, which cannot be mass-produced, which makes the cost of treatment unaffordable. Therefore, the next step of CAR-T cell therapy is to find a way to find T cells that can be used by several people, so as to reduce the cost of the customization process, but so far, humans still cannot overcome the rejection of allogeneic transplantation.
The side effects of CAR-T cell therapy
Although CAR-T cell therapy drives the body's immune response to fight cancer cells, it also has a chance of causing side effects. Because a large number of T cells are injected into the human body in a short period of time, the immune system will still be disturbed to a certain extent. And when CAR-T cells attack cancer cells, a violent immune response will also occur. However, the length of time and symptoms of side effects are not the same for each person, and the side effects can be roughly divided into three categories. The first type is Inflammatory factors, leading to a series of symptoms such as fever, chills, rapid heartbeat, shortness of breath, dizziness, nausea, vomiting, diarrhea, and joint pain. In the most severe cases, coma may also occur. The second type is neurotoxic syndrome, a symptom which caused by immune cells "accidentally injuring" the central nervous system. When the nervous system carries the same type of antigen as the cancer cells, or the cancer cells are near the nervous system, the nervous system will be accidentally injured. The patient will develop headaches, tremors, muscle stiffness, convulsions, unresponsiveness, poor balance, or unconsciousness. The third type is side effects from other treatments, such as allergic reactions during infusions, or immune system reactions after treatment. weaken. All in all, CAR-T cell therapy has the risk of acute side effects, so it needs to be observed in the hospital for several days after treatment.
The latest research direction of CAR-T cell therapy
Since CAR-T cell therapy is a new technology developed in 2019, there are still many technical problems waiting to be overcome, which has attracted many scientists to invest in research. This article selects two recent breakthrough studies to share with you.
Science Advances, April 8, 2022: CAR-T cells are encapsulated in a special hydrogel containing cell-stimulating factors that increase cell activity. Encapsulating CAR-T cells in hydrogel allows the body to maintain a certain concentration of cells and maintain cell activity.
Science, December 16, 2022: Make CAR-T cells have their own stimulants, and add a gene to CAR-T cells so that they can secrete substances that stimulate their own excitement when they come into contact with cancer cells.
TCR-T cell therapy
The name of TCR-T cell therapy is similar to CAR-T cell therapy. TCR is the abbreviation of T cell receptor, which is a protein that can help T cells distinguish friend from enemy. By means of computer algorithms (guess how to modify the genes of T cells) and gene editing technology (Crispr-Cas9), humans can make T cells exhibit TCR. Even if MHC-I is reduced, immune cells can Navigate proteins to find cancer cells. In addition to the similar naming methods, TCR-T cell therapy and CAR-T cell therapy also have the same side effects to be overcome. However, this new technology published in Nature in November 2022, is expected to treat cancers with solid tumors such as lung cancer, breast cancer, and colorectal cancer.
Cancer vaccines
Cancer vaccines are the direction that many biotechnology companies have invested in research in recent years, such as Moderna and BNT, the two biotechnology companies that have developed COVID-19 vaccines. The initial research directions of these two companies were both cancer vaccines. During the process, they just developed mRNA technology. As a result, they happened to meet the outbreak of COVID-19, so the two companies turned to research COVID-19 vaccines. The reason why the COVID-19 vaccine can be launched in just one year can be said to rely on previous research results in the field of cancer vaccines. It is not an exaggeration to say that the COVID-19 vaccine is an additional product of cancer vaccines.
The cancer vaccines are different from vaccines that the general public is familiar with. Vaccination is not to "prevent" disease, but to prevent the "relapse" of disease. Take the hepatitis B vaccine as an example. Everyone is exposed to the same virus, so the ingredients of the vaccine are also the same. But in the case of cancer, the gene mutation of each cancer cell is different. It is tailor-made for each patient, so it is impossible to make a vaccine for the general public.
However, cancer vaccines are not a research direction that has only emerged in the past few years. As early as 13 years ago, in 2010, the world's first cancer vaccine, Provenge vaccine, which also known as Sipuleucel-T vaccine was born. This vaccine is mainly used to treat prostate cancer. But it is a pity that the development of cancer vaccines hit the wall in the next ten years, no second vaccine has been on the market.
Having said that, if broadly defined, there are two vaccines that are familiar to the public can also be positioned as cancer vaccines, namely the human papillomavirus (HPV) vaccine and the hepatitis B vaccine. HPV vaccine can effectively reduce the risk of cancer because it can prevent viral infection. The hepatitis B vaccine can prevent hepatitis and cirrhosis, and indirectly reduce the chance of liver cancer.
All in all, because of the failure experience of more than ten years, many researchers or scientists still doubt the feasibility of cancer vaccines, but many people are optimistic. According to a review report in Lancent Onology in October 2022, there are many mRNA vaccines underway or about to undergo clinical trials, covering cancers such as lung cancer, colorectal cancer, pancreatic cancer, prostate cancer, ovarian cancer, and head and neck cancer.
At present, there are many data pointing out the brilliant performance of cancer vaccines. When cancer vaccines are combined with immunotherapy, the risk of recurrence or death of patients with advanced melanoma is reduced by 44%. On May 10, 2023, Nature magazine published the results of a phase I human clinical trial of a pancreatic cancer vaccine, showed that some of the subjects produced cancer cells that could fight tumors. Pancreatic cancer is very difficult to treat, and it is also known as the "cancer king", so this result is very important and fell exhilarating. And in April 2023, Moderna told the British Guardian that they are confident that mRNA vaccines for cancer, cardiovascular disease and autoimmune diseases will be made before 2030. The chief of the medical officer even says the the cancer vaccines may be possible ready within five years.
Bacterial therapy
"Bacteria are not necessarily enemies, they may be allies"
In 1891, American doctor William Coley injected Streptococcus pyogenes into the tumor for the first time, completely eliminating the cervical sarcoma cancer in the patient. In the following 30 years, Dr. Coley used bacterial therapy to save more than 1000 patients. However, at that time, Dr. Coley could not explain the principle of the therapy, and even the cause of the tumor could not be explained at that time, so he was opposed by the academic circles. In modern times, 100 years later, the academic community was finally able to explain the principles of bacterial therapy, and called Ke Lizun the father of immunotherapy.
In the past 10 to 20 years, as the relationship between cancer and immunity has gradually become clear, bacterial cancer therapy has made a comeback, and scientists have used their favorite strains to conduct cancer treatment experiments. In this article, three kinds of bacteria that are more popular and have been clinically tested are selected to share with you.
Listeria monocytogenes
Listeria monocytogenes is an intracellular pathogen that can grow inside human cells. Phagocytes that invade the human body, grow and multiply inside the cell, and present specific antigens on the surface. Humans use gene transfer to make Listeria show specific antigens, such as mesothelin, which only appears in pancreatic cancer and ovarian cancer. Use the specific antigens displayed by bacteria to exercise the immune cells of the human body, so that the immune cells can respond to the antigens carried by cancer. In 2015, researchers successfully used Listeria that had been weakened to express mesothelin to treat patients with end-stage pancreatic cancer.
Clostridium butyricum
Clostridium butyricum is a probiotic bacteria developed in Japan in 1933, also known as "butyric acid bacteria" or "CB bacteria". As a probiotic, Clostridium butyricum not only maintains gut health and relieves depression, but also significantly increases the response rate of immune checkpoint inhibitors (enhancing the effect of immune boosters). On February 28, 2022, a paper published in Nature pointed out that in patients with end-stage kidney cancer, if thalidomide butyrate is used together with immune checkpoint inhibitors, the patient's response rate can increase by 58%. Compared with the 20% response rate of immune checkpoint inhibitors alone, it is clear that the combination of the two is more effective.
Mycobacterium tuberculosis
Mycobacterium tuberculosis is an aerobic microorganism, which is the culprit that causes tuberculosis in humans. In 1882, German microbiologist Robert Koch was awarded the Nobel Prize in Physiology or Medicine in 1905 for his discovery of Mycobacterium tuberculosis as the causative agent of tuberculosis.
In 1900, Albert Calmette and Camille Guérin began research on a tuberculosis vaccine. The research process can be said to be full of twists and turns, and the experiment process was interrupted many times due to the First World War. In the end, it took them nearly 20 years to develop a vaccine to overcome tuberculosis - Bacille Calmette-Guérin(BCG). The BCG vaccine is an active vaccine made from weakened tuberculosis bacteria, which can produce resistance to tuberculosis.
In 1959, a Nature paper accidentally discovered that mice given BCG could greatly delay the growth of tumors. So on the basis of BCG, the researchers developed another drug, Onco-BCG. If Onco-BCG is injected into the bladder, it can treat early bladder cancer or prevent bladder cancer recurrence. After Onco-BCG is injected into the human body, it can call more white blood cells to the bladder and stimulate the activity of white blood cells to kill cancer cells. Onco-BCG itself also has the effect of directly inhibiting tumor growth.
Conclusion
After introducing so many kinds of immunotherapy, I believe everyone has realized the importance of immunotherapy for the treatment of cancer. Scientists are also optimistic that under the treatment of immunotherapy, cancer may have the opportunity to transform the deadly killer of human beings into a common chronic disease. However, no matter what kind of immunotherapy, there is still a long way to go, especially the high cost of treatment is also a difficulty waiting for researchers to overcome.
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