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Introduction to Immunotherapy

What is immunity?

Immunity refers to the physiological system in which the human body recognizes its own substances (autologous cells) and foreign substances (non-self foreign substances) and eliminates foreign substances. The so-called cancer refers to the cancerous substances produced by the uncontrolled proliferation of normal autologous cells due to DNA damage. The immune system will recognize the cancerous cells as alien substances.

The immune cells responsible for eliminating cancer cells include natural (NK) cells, natural killer (NKT) cells, and killer T cells (cytotoxic cells, also known as CTLs); among them, killer T cells are the most evolved, and T cells are different from other immune cells Because it has the ability to learn. Because the learning ability of killer T cells can mark cancer cells and generate a "cancer antigen" response, inducing a strong anti-cancer effect.

What is Immunotherapy?

"Cancer immunotherapy" is a method of strengthening the immune response to treat cancer. In addition to the above-mentioned NK cells, NKT cells, and killer T cells, immune-related cells include macrophages, helper cells, and B cells. As long as the activation of any of these cells is used to achieve the purpose of treatment, it can be called "cancer immunotherapy". "Cancer immunotherapy" is divided into antigen non-specific and specific. Cancer peptide vaccine therapy is a therapy that increases killer T cells (activates them) to prevent cancer recurrence or proliferation, and is a specific immunotherapy for specific peptides.

At present, immunotherapy is divided into two types, cellular immunotherapy (alias immune cell therapy) and molecular immunotherapy (alias immunotherapy). In Taiwan, molecular immunotherapy can be applied by a doctor. Only cellular immunotherapy is not yet open due to laws and regulations. , need to go to other countries, such as China, Japan. Japan's experience in implementing cellular immunotherapy and its high level of medical technology have also become one of the main choices for patients in Taiwan.


Classification of immunotherapy?

Immunotherapy is divided into immunodrug therapy & immune cell therapy.

Remarks: This form is made by medical assistants, and the content is for reference only. For actual drugs and medical conditions, please follow the information provided by professional physicians and pharmaceutical companies.

Immune cells are mainly white blood cells differentiated from stem cells. 95% of white blood cells are granular balls, and 5% are lymphocytes composed of single balls. Lymphocytes are divided into B cells, T cells, NK cells, and NKT cells. Currently widely used immune cell therapy is the use of NK cells, T cells, NKT cells and dendritic cells.


Immune cell therapy can be broadly divided into two types. One is non-specific immune cell therapy that activates and proliferates immune cells in situations where the characteristics of cancer cells cannot be recognized. Another type of specific immune cell therapy that allows immune cells to recognize cancer cells. These two therapies are related to NK, DC, T cells or B cells.


According to recent studies, the same αβT cells and γδT cells can be isolated, and it has been confirmed that most of the T lymphocytes in the blood are αβT cells, and a few percent of them also contain γδ receptors. Recently, it is believed that T cells cannot convey antigen information and do not have the idea of attacking cancer cells, but this kind of γδT cells does not need to be prompted by dendritic cells and can attack tumors like NK cells, so it is now more and more institutions are doing such therapy.

Non-specific immune cell therapy

1.cytokine therapy

Cytokine is a substance released by immune-related cells, which has the effect of promoting the activation and proliferation of immune cells. Among them, interleukin2, innta-roikinn12, interferon (1FN), and tumor necrosis factor (TNF) are included, and the administration method is drip administration.


2. LAK= Lymphokine-activated Killer cells therapy

This is a therapy started in the United States in the 1980s, and it is the ancestor of various immune cell therapies. It mainly takes a large number of lymphocytes in the patient's body and then deactivates them with interleukin2, followed by injection back into the patient's body. The main reason is that patients increase NK cells. For patients, the sudden increase of lymphocytes or interleukin2 in the body will burden the body. Therefore it will be carried out by the CD3-LAK therapy described later.


3. NK= Natural Killer cells cell therapy

NK cells that directly attack cancer cells are extracted from the patient, activated and increased in number with interlukin2, and injected into the patient. Compared with the past, the current NK therapy has increased from dozens of times to thousands of times. There are currently many clinics in Japan that are performing this type of therapy. For example, the well-known Seta Clinic is in progress.


4. CAT=CD3-Activated T cells=CD3-LAK= αβT cell therapy

This therapy has many names, but they all have the same connotation, and it is currently the most common therapy. A therapy that administers anti-CD3 antibody (an antibody that stimulates the CD3 molecule of T cells) and interlukin 2 to T cells attacking cancer cells to activate and proliferate them. Compared with CTL, the ability of each cell will not be more powerful, but it can increase a lot. Such T cells mainly attack cancer cells, but CD8-positive T cells are also found in αβ-type cell receptors. These cells produce cytokine substances that are effective against tumors. The main body of this therapy is cell-damaging T cells, and it can also assist in the activation of T cells or NK cells. There are many hospitals in Japan that are carrying out this therapy, and there are also clinical trial plans, such as the Tokyo Women's Medical University Medical Center and so on.


5. Allogeneic Lymphocyte Therapy

This therapy is to use other people's lymphocytes to infuse the patient to stimulate the patient's own lymphocytes and increase their lethality. However, instead of administering lymphocytes targeting cancer cells, it mainly depends on the patient's own immune system. This therapy started from the white mouse experiment in 1972 at Harvard University. According to the same white mouse lymphocyte injection, it proved to be effective, followed by other animal experiments, and then to human clinical trials. The results confirmed that injecting other people's lymphocytes will increase the attack effect of the patient's own lymphocytes on cancer cells.

This treatment is a type of non-specific immunotherapy in which dendritic cells are given to cancer cells after they are recognized and attacked using NK cells. Taking an individual as an example, the lethality to cancer cells is more powerful than that of T cells. The advantage of this treatment is that it uses other people's lymphocytes, so blood does not need to be drawn from the patient. The injection volume at one time is about 20cc~40cc, so the burden is not too heavy. It should be noted that since the lymphocytes of other people are administered, attention should be paid to the problem of virus infection.

specific immune cell therapy

1. CTL = Cytotoxic T Lymphocytes therapy

Take the T cells that attack cancer cells from the patient, and add them to the patient's own cancer cells or anti-cancer antigen proteins, so that the T cells can learn to recognize cancer cells, cultivate and activate anti-CD3 antibodies with interleukin2, and produce a large amount of cell damage. A therapy in which T-lymphocytes with specific characteristics are injected back into the patient.

There are two types of CTL therapy, T-CTL with antigen removed from the patient, and P-CTL with artificial antigen. Compared with autologous cancer antigen, it is considered to be more effective. This T-CTL therapy is limited to the removal of antigens from relatively large tumors by surgical methods. P-CTL therapy must also recognize cancer cells through MHC molecular antigens to be effective. This is the shortcoming of CTL therapy.


2. TIL = Tumor Infiltanting Lymphocytes therapy

The lymphocytes removed from the tumor contain T cells that are activated against cancer antigens. After being collected from the tumor, it is cultured with interleukin2 and injected back into the patient's therapy. It's just that the method of isolating lymphocytes from tumor tissue is cumbersome, and it needs to be injected back after long-term culture, so the effect on tumors needs to be strengthened. The current new method is to try to use TIL cells and cancer cells to co-culture, so that it can have a stronger effect on tumors, but it is currently being demonstrated.


3. DC = dendritic cell therapy

DC is one of the antigen-prompted cells, and its function is to stimulate and activate T cells to become killer T cells, so that they can attack cancer cells. A DC can stimulate hundreds to thousands of lymphocytes, which is quite efficient. However, the number of DCs only accounts for about 0.1-0.5% of the white blood. The currently used DC therapy is a new technology that takes more immune cell single balls from the blood than DC to separate components to obtain a large amount, and then differentiates DC with drugs.

For DC therapy, there is currently a DC vaccine therapy that uses tumor antigens in the patient's body or artificial antigens to mix, so that DCs have the ability to activate T cells more easily and then inject them back into the patient. And DCI therapy that obtains a large number of DCs from patients and then injects them back after culture. For inoperable patients, DCI therapy is also available.

This kind of DC therapy, in order to make DC have a better antigen prompting effect, a CHP compound vaccine was developed. This is a synthetic vaccine of the Pullulan carbohydrate-decapped HER2 cancer antigen protein. In animal experiments, after injection of CHP vaccine, DC and other antigen-prompting cells are more efficient in prompting cancer antigens, and NKT's attacking effect on cancer cells also has a significant growth. At present, this clinical trial is being conducted at Mie University in Japan, mainly targeting breast cancer, esophageal cancer, and lung cancer. Note the qualifications required for clinical trial volunteers. In addition, private institutions, such as Medinet Co., Ltd. have a technology for optimizing DC (Cell Loding System) or a technology for inducing CTL with Zoledronic acid developed by Seta Clinic.

4. Neoantigen = neoantigen

Dendritic cells are also used. The difference lies in the way of antigen prompting. In this method, the cells of the patient's living tumor tissue must be obtained for genetic testing. After confirming the surface antigen of the cancer cells, tailor-made, and then educate the dendritic cells. Let T cells get more information about the tumor, and then achieve the goal of attacking cancer cells. In July 2017 and June 2018, the world-renowned biotechnology magazines Scinece and Nature Medicine mentioned relevant clinical data, but it should be noted that the results of the treatment were also combined with immune checkpoint inhibitors .

Non-specific and specific combined immune cell therapy

1. CTL + NKT therapy

This is the latest proven therapy using NKT cells. In the past, CLT was used to allow T cells to recognize cancer cells and then injected back into the body for treatment. However, the MHC antigen molecule of the cancer is always targeted and attacked. If the cancer cell loses the MHC antigen molecule, it cannot be recognized and ignored. Therefore, NKT cells are used to attack cancer cells that have lost MHC antigens. Also because of this situation, NKT cells and NK cells have the same function, and DC cells receive antigen prompts from cancer cells to attack cancer cells immediately. Therefore, one therapy is to make two kinds of immune cells complement each other, and it is also a therapy that is currently expected. Currently, Chiba University School of Medicine is conducting clinical trials on this therapy.


2. γδT cell therapy・BAK therapy (BRM Activated Killer)

γδT cells only account for a few percent of lymphocytes, and this kind of cells will actively attack cancer cells without the instruction of DC. In addition, γδT cells have anti-tumor effects, and will produce cytokines such as INT-γ, but they will gradually decay with age. This treatment was administered by Dr. Ebina Takusaburo of the Miyagi Prefectural Cancer Center Research Institute. γδT cells were extracted from NK cells in the blood containing CD56-positive lymphocytes, and injected back into the patient after two weeks of culture. developed. The clinical results showed that two patients were relieved, one patient was partially relieved, and ten patients remained stable. Of the four patients treated with BAK therapy to prevent metastasis after surgery, two showed no signs of recurrence.

Immunotherapy clinical trial information in teaching hospitals across Japan (updated from time to time)
Private medical institutions that can provide immunotherapy in various parts of Japan (Irregularly updated)

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