Introduction to cancer immunotherapy using highly active NK cells

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What is highly active NK cell therapy?

Among cancer immunotherapies, the New City Osaki Clinic provides “activated lymphocyte therapy”, more specifically, “Highly active NK (natural killer) cell therapy” in which NK cells are activated to the maximum extent by a method different from conventional ones.
In highly active NK cell therapy, lymphocytes are collected from patients’ blood and among these lymphocytes, NK cells that play a role in initially attacking abnormal cells such as cancer cells are cultured and grown in large amounts, and their ability to kill cancer is further enhanced (activated). NK cells are then returned to patients’ bodies in order to strengthen their immunity.

Effect sought in highly active NK cell therapy

1. Effect in spreading throughout the body a large amount of activated NK cells and T cells that directly attack cancer cells
→ Cancer treatment, prevention of recurrence

2. Effect in rebuilding the strength of the whole body to fight cancer by enhancing patients’ immunity
→ Improvement of QOL (quality of life)

In cancer immunotherapy at this clinic, we not only prioritize therapeutic effects, but we also make efforts not to lower patients’ quality of life after the treatment. We aim at improving the quality of the unique elements of each patient’s life, as well as the quality of his/her social life.

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Characteristics of highly active NK cell therapy

1. Ten to twenty billion activated lymphocytes are administered at once.
2. NK cells, which are considered to be difficult to increase as well as T cells (particularly, cytotoxic T cells), are proliferated to a large amount and activated.
3. These cells contain a large amount of molecules that are capable of killing or damaging cancer cells such as TRAIL and NKG2D.
4. This therapy is more effective when combined in treatment with anticancer agents.
5. There are no side effects other than mild fever.
6. Patients can lead their daily lives while receiving treatment (patients do not have to be hospitalized for this treatment).

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Role of NK cells

In “highly active NK cell therapy”, the focus is not on the culture of T cells, which are involved in acquired immunity, but on the culture of NK cells involved in natural immunity, which patrol throughout the body and attack abnormal cells immediately as a troop responsible for the initial attack. The anticancer effects of NK cells that have been confirmed to date are described below.

1. The effect in removing cancer cells that are generated every day

Even in a healthy person’s body, several thousand cancer cells are considered to be generated and eliminated per day. Mainly NK cells are thought to detect and eliminate abnormal cells (cancer cells).

2. The effect in preventing recurrence and metastasis of cancer

NK cells are considered not only to prevent the development of cancer but also to inhibit its recurrence and metastasis (cancer spreads to distant areas through blood vessels).

3. The effect in attacking cancer cells which T cells cannot attack

The cancer cells that survive make themselves invisible to the T cells instructed to attack them (CTLs: cytotoxic T lymphocytes) by changing themselves over time in order to avoid their attack (MHC class I molecules disappear). NK cells are considered to attack such cancer cells rather effectively. On the other hand, NK cells are known to be less likely to attack cancer cells with MHC class I molecules, but this weak point can be overcome by enhancing the cancer-killing molecules in NK cells.

4. The effect in specifically attacking the cancer cells with antibodies

There is a cancer therapy called, “antibody therapy”, using antibodies that respond only to cancer cells and inhibit their growth (for example, Rituxan, Herceptin). One of the reasons for the efficacy of antibody therapy is thought to be the involvement of NK cells. It is confirmed in experiments that NK cells bind to and activate the Y-shaped tails of antibodies (called Fc fragments), thereby killing cancer cells. This is called ADCC (antibody-dependent cell-mediated cytotoxicity) activity, an efficient mode of killing cancer cells, which does not involve T cells (Figure 1). In the near future, antibody therapy and NK cell therapy will be combined in cancer treatment.

Figure 1

5. The effect in enhancing immune response to cancer

Other than attack on cancer cells, important actions of NK cells on cancer immunity have recently been discovered and are attracting attention. When stimulated by NK cells, dendritic cells reportedly generate a large amount of CTLs that attack cancer cells. In addition, dendritic cells stimulated by NK cells were shown to do so 100 times more effectively than regular dendritic cells. When successfully combined with anticancer agents, a large amount of highly active NK cells are more likely to induce CTLs against cancer antigen.

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Difference from other activated lymphocyte therapy

There are the following differences between the “highly active NK cell therapy” developed by the New City Osaki Clinic and other activated lymphocyte therapies.

“T cell (T lymphocyte) therapy”

It is a pioneering lymphocyte therapy in which T cells that originally account for 70% of the peripheral blood lymphocytes are stimulated and proliferated by a CD3 antibody and IL-2. T cells function in acquired immunity. Therefore, they cannot function unless they are educated about which cells to attack and one T cell can fight only one cancer antigen. T cells as a whole can be proliferated by a CD3 antibody, but this results in only limited amount of T cells that attack particular cancer. However, even when activated T cells are nonspecific, overall capability to attack cancer cells is enhanced and therefore, immune response to cancer can be promoted.
With recent advancements in research, new methods have been tried in which T cells are collected directly from cancer lesions to increase the specificity to cancer antigens, or in which T cells are genetically equipped with molecules that recognize cancer antigens and increased to a large amount for use.

“NKT cell therapy”

NKT cells account for as low as 0.1% of the peripheral blood lymphocytes. NKT cells respond to glycolipid bound to a single antigen-presenting molecule called CD1 and are difficult to increase. Other than their antitumor activity, NKT cells were reported to increase NK cells and cytotoxic T cells. Research on NKT cells is being continued, but there are many challenges to solve in their proliferation by culture or efficacy of activation because of their scarcity.

“γδ (gamma delta) T cell therapy”

Many γδT cells are present in intestinal mucosa or skin, but they account for only a few percentages of the peripheral blood lymphocytes. Although they have antitumor effects, there are many unknown aspects in these effects. They were shown to be increased by bisphosphonates, the drugs used for osteoporosis, and studies are being conducted for their clinical application.

“NK cell therapy at other facilities”

NK cells are considered to be difficult to increase. At many facilities, the number of NK cells administered in one dosing seems to be up to 1 billion. As we will discuss separately, data have shown that it is quite difficult to obtain targeted level of efficacy by the administration of 10 billion or less.
In highly active NK cell therapy at the New City Osaki Clinic, our unique culture method is used and 4 to 10 billion NK cells are administered at once. Even though this highly active NK cell therapy and NK cell therapies provided at other facilities all belong to the same NK cell therapy, ours is completely different from others in method for culture, number of cells administered and level of activation. Therefore, please consider our NK cell therapy as a different treatment method from those used at other facilities.

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Cancer immunotherapy

Immune system | Cancer immunotherapy | Highly active NK cell therapy | Problems of highly active NK cells | Characteristics of highly active NK cells | “immunity-enhancing effect” of highly active NK cells | Recommendation of highly active NK cell therapy