N K Cell immunotherapy – A new era in the treatment of cancer

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What is NK-cell therapy?

Trillions of cells replicate in a person every day. Under the influence of carcinogens (smoking, ionizing radiation, Helicobacter pylori, etc.), about 500,000 to 1 million cells can mutate during the replication process every day. Some mutant cells further become cancer cells.

Immune legion

After thousands of years of evolution, the human body has formed a sophisticated defense system, established a powerful immune corps, and stocked a large number of elite soldiers, always protecting us and keeping us away from cancer. Among them, the bone marrow is the headquarters of the immune system. Here, hematopoietic stem cells differentiate into immune fighters with different functions. They have their own army territory and job responsibilities.

There are three main armies:

1. Core Legion: Lymphocyte

T lymphocytes Thymus-dependent lymphocytes, the main lymphocytes in blood and recirculation

B lymphocytes develop in the bursa of bursa or its isoactive organs (bone marrow), which can differentiate into antibody-producing plasma cells after being stimulated by the antigen

NK cells, LAK cells do not need the killing effect of antigen sensitization

2. Auxiliary Legion: Antigen presentation

Mononuclear-macrophage phagocytosis, present TD antigen, initiate immune response, anti-tumor effect, secretion of bioactive media

DC cells are a group of heterogeneous cells with the strongest antigen presentation function and are the only professional antigen-presenting cells that can activate naive T cells

3. Other immune cell legions

Neutrophils, eosinophilic / basic granulocytes and mast cells, platelets, red blood cells.

What is NK Cell?

Immune Relay Battle: The First Stick-NK Cell

The immune battle in our body is exactly the same as the anti-enemy war deduced in the movie. Like a relay race, it requires the clear division of labor of the three armies, a meticulous combat plan, and coordinated operations to wipe out the enemy in one fell swoop.

In the battle against cancer cells, natural killer (NK) cells bear the brunt. It is the first to directly kill cancer cells when they reach the tumor micro environment while secreting secret weapon chemokines to recruit dendritic cells (CD103 + DC). Then, activated dendritic cells carry tumor antigens to the lymph nodes, presenting the characteristics of cancer cells to killer T cells. T cells then rush to the battlefield to kill cancer cells together with NK cells.

NK Cell with strongest killing effect

NK cells
Full name: Natural Killer Cell

Source: Derived directly from bone marrow, the development of which depends on the microenvironment of bone marrow

Function: The target cells killed by NK cells are mainly tumor cells, virus-infected cells, larger pathogens (such as fungi and parasites), allotransplanted organs and tissues.

The full name of NK cells is Natural Killer Cell (NK), which is the third group of lymphocytes in parallel with T and B cells in the core cell legion. NK cells are large and contain cytoplasmic particles, so they are called large-particle lymphocytes. It has three biggest characteristics:

First, it is the innate immune system of the human body. It is definitely the soldier in the forefront. Almost all tumor cells will be attacked by NK cells first.

Second, it has a broad-spectrum antitumor effect, does not require tumor-specific recognition, and is not restricted by the major histocompatibility complex (MHC) inhibitory activity on the cell surface. The startup time is the fastest, and T cells need to be presented with antigens before they can distinguish between “enemy and enemy”.

Third, the situation feedback is timely. Once the “enemy situation” is found, it is quickly “reported” and the immune defense and immune killing functions of the entire immune system are activated.

Therefore, the cancer-killing effect is powerful.

However, the number of NK cells in the human body is relatively small, accounting for about 15% of the total number of lymphocytes in the peripheral blood, and about 3% to 4% in the spleen. They can also appear in the lung, liver and intestinal mucosa, but in the thymus, lymph nodes and Chest catheter is rare.

How NK cells kill cancer cells?

NK cells play a key role in the first line of defense against cancer. NK cells have three anti-cancer effects:

One is the direct killing of tumor cells, killing tumor cells by releasing perforin and granzyme or death receptors; the second is that it acts as a regulatory cell of the immune system by activating cytokines and chemokines, activating T cells, etc. The lethal effect.

The third is the formation of ADCC (antibody-dependent cell-mediated cytotoxicity). When B cells find cancer cells, they will quietly leave specific IgG antibodies on the cancer cells as a mark to remind NK cells to see this mark. NK cells see each other and kill them. With the help of macrophages and B cells, the morale of cancer-killing increased greatly.

NK cells annihilating cancer cells

NK cells exist in human blood and are “first responders”. It is like a policeman who has been on duty in the body. As the blood runs around, NK cells continue to contact other cells while patrolling. Once an abnormality is found in the body Cells, immediately stable, accurate, ruthlessly wait for a time to deal with. They attack and release cytotoxic particles containing perforin and granzyme on the target cell membrane before T cells are deployed, triggering the self-destruction of cancer cells. They can also eliminate cancer stem cells circulating in the body and help prevent metastasis.

NK cell-based immunotherapy

Although they can quickly defend and directly attack tumor cells, NK cells are only a small part of the immune system, accounting for only 10% of white blood cells. And the study found that after 25 years of age, human immunity declines and the number of NK cells become less. The number and activity of NK cells in tumor patients and patients after tumor surgery have changed to a certain extent, and they cannot effectively exert an anticancer effect.

Researchers are now focusing on “adoptive” NK cell therapy-collecting NK cells from closely related donors and injecting them into patients. This has proven to be safe, and unlike T cell therapy, NK cells do not cause graft-versus-host disease in recipient tissues.

The current international NK cell strategies for tumor immunotherapy are:

1. In vitro activated autologous or allogeneic NK cell therapy;

2. Combine NK cells and monoclonal antibodies (such as immune checkpoint inhibitors) to induce antibody-specific cytotoxicity;

3. Construct CAR-NK cell immunotherapy.

Activate NK cell auto receptors: Block inhibitory receptors on NK cell membranes with antibodies, or stimulate activa
ting receptors to increase NK cell lysis activity

In combination with immune checkpoint inhibitors: checkpoint therapy combined with other NK-guided immunotherapy can target multiple types of tumors that do not currently respond to existing therapies.

NK cells modified by chimeric antigen receptor: can significantly improve the specificity of NK cell efficacy. This idea is similar to the construction of CAR-T: CAR includes extracellular recognition domains (such as scFv) to recognize tumor-specific antigens; a transmembrane domain, and an intracellular signaling domain (CD3ζ chain) can induce NK cells activation.

What is the difference between NK cell and T cell therapy?

In the field of cancer immunotherapy, people have been focusing on mobilizing anti-tumor T cells. Currently, the FDA has approved two CAR-T cell therapies.

Both T cells and NK cells can recognize and kill cancer cells, but they proceed in very different ways.

T cells need to “present” some parts of their target cells to other immune cells in order to recognize them as foreign cells and to aggregate T cells into attack patterns.

NK cells recognize the pattern of cancer cell changes and are the first line of defense of the immune system. Unlike T cells, they directly detect and destroy infected and malignant cells without having to be activated or “trained” to respond to cancer cells. However, it is now well known that exposure to cytokines, which are components of the immune system, activates NK cells more effectively.

Natural killer cells are shown in green attack mouse tumors. NK cells may be the key to cancer immunotherapy. Blue shows blood vessels. Image source: Dr. Michele Ardolino and Dr. Brian Weist

Advantages of NK cell therapy

1. Immune cell therapy is the fourth treatment method after surgery, chemotherapy and radiotherapy. NK cell therapy combined with radiotherapy and chemotherapy can effectively remove tumor cells that cannot be completely removed by surgery;

2. NK cell therapy combined with radiochemotherapy can improve the efficacy of radiochemotherapy and reduce side effects;

3. For advanced cancer patients who are not suitable for surgery, radiotherapy, or chemotherapy, NK cell therapy is a better choice;

4. Regular treatment with NK cells after surgery can prevent the recurrence and metastasis of cancer;

5. Relieve cancer pain, improve sleep, improve patient’s quality of life, and extend patient’s life cycle;

6. For sub-healthy people, the use of NK cell therapy can reduce the risk of cancer.

NK Cell Therapy International Update

Japanese NK cell immunotherapy

In order to improve the activity and number of NK cells in the body, Japanese scientists have invented a multiplier method, which is to extract 50ml from human blood, isolate a small amount of NK cells and then expand the culture to increase the number to the original 1000 times, the number reaches 1 billion to 5 billion and is then returned to the body, a large number of NK cells will circulate 3000 to 4000 times with the blood system, killing cancer cells, aging cells, diseased cells, bacteria and viruses in the body Once again, to achieve the purpose of anti-cancer, improve immunity and prolong survival.

American NK cell immunotherapy

The United States included NK cells in cancer immunotherapy trials!

A woman with acute myeloid leukemia (AML) is dying after repeated chemotherapy failures. As a final attempt, she received an experimental cell infusion of natural killer (NK) cells donated by her son. After 4 days, the osmotic skin lesions disappeared, and soon she entered a state of relief.

Although NK cell therapy is still only in early clinical trials in the United States, clinical research is increasing.

A clinical trial led by Washington University in St. Louis showed that approximately 12 patients with AML and myelodysplastic syndrome (MDS) received NK cells. Half of the patients entered the remission period.

At present, MD Anderson at Dana Faber Cancer Institute is conducting a clinical trial, which will test the efficacy of NK cell therapy in patients with hematological tumors that relapse after stem cell transplantation. Patients who want to know the details can call +91 96 1588 1588.

Who is suitable for NK cell therapy?

1. Patients with poor physique before tumor surgery, slow recovery after surgery, and fear of occult cancer cells not being completely eradicated.

2. After radiotherapy and chemotherapy, the immune system is low, the side effects are obvious (such as loss of appetite, nausea, hair loss, skin inflammation, etc.), and patients expect to increase the effect of chemoradiation.

3. Patients who wish to use various treatments to achieve therapeutic effects due to fear of the side effects of radiotherapy and chemotherapy.

4. Patients with advanced cancer cells have spread throughout the body, but conventional treatment methods have been powerless, and patients who expect to prolong survival and improve quality of life.

The treatment process of NK cell therapy

1. Blood collection: Extract 30–50 ml of peripheral blood of cancer patients and extract mononuclear cells;

2. Laboratory culture: In the laboratory, conduct NK cell induction and expansion for a period of 5-7 days;

3. Return: After the NK cell culture is completed, it is returned to the cancer patient like an infusion.

Treatment case of NK cell therapy

Case Source: An authoritative NK cell therapy clinic in Japan

Ms. Zheng, 50, was diagnosed with advanced pancreatic cancer (pancreatic tail), transferred to the liver, lungs, and pleura, and was diagnosed with cancerous peritonitis (chest wall, multiple nodules in the lungs). . After one cycle of Gemcitabine Gatige, the effect was not satisfactory, CA19-9 rose from 257,531 to 318,417. On the advice of the doctor, the whole genome was sequenced, and the result did not have any meaningful mutations. The doctor said that she had three months to six months at most. According to expert recommendations, Ms. Zheng began to reinject highly activated NK cells at a frequency of once every two weeks.

Immediately after finishing the first return, Ms. Zheng’s most obvious feeling was that she felt full of energy. She was always weak, and the pain symptoms were alleviated. With appetite, you can eat some light food.

Unexpectedly, the treatment was very smooth. After the first treatment, CA19-9 was directly reduced to 7355. After the fourth highly activated NK cell treatment, it has dropped to 141.

At the end of 2016, the rechecked CT images showed that metastatic lesions such as liver and lung bronchial lymph nodes had disappeared. Pancreatic cancer at the primary site has also shrunk by more than half.

Although it has not been fully recovered, the treatment process is very smooth. Before starting treatment, the worst preparations have been made, and even a course of treatment may not be able to persist, but by the end of the first course of treatment, the patient’s physical condition has greatly improved.

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