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NK Cell Immunotherapy and Related Immune Checkpoint Inhibitors
11:20 - 14 กุมภาพันธ์ 2563

What is NK cell

NK cells are a type of MHC-independent lymphocytes that have a strong killing effect on tumor cells. Their recognition of tumor cells mainly depends on the cross-regulation of their surface-activating receptors and inhibitory receptors. After identifying tumor cells, NK cells kill tumor cells by releasing killing mediators of perforin and granzymes to target cell apoptosis, expressing membrane TNF family molecules to induce target cell apoptosis, and antibody-dependent cytotoxicity.

Advantages of NK cells

NK cells are considered as effector cells that have the potential to enhance their anti-tumor capabilities through CAR modification because of their special recognition mechanism of target cells, short physiological cycles, and extensive tumor-killing ability.

However, due to the decrease in the number and quality of NK cells in tumor patients and the existence of tumor escape mechanisms, their antitumor functions in vivo have not been fully exerted. CAR modification of NK cells is expected to enhance its ability to target tumor cells and develop effector cells with strong anti-tumor effects.

The main advantages of NK

  1. No need to activate endogenous cytotoxic receptors of NK cells
  2. Selective identification of tumor-associated antigens
  3. Organic antigen-specific target cell lysis
  4. It has obvious advantages for the treatment of solid tumors. Solid tumors show different degrees of tolerance to unmodified NK cells, but they are sensitive to antigen-dependent NK cells.

NK cells and important immune checkpoint inhibitors

Certain activated NK cells express PD1 and CTLA4. Researchers have detected that NK cells express PD1 in patients with multiple myeloma. The use of PD1 mAb (CT-011) can repair NK cell-mediated antitumor effects. In addition, IgG1 mAb using PDL1 may also stimulate NK ADCC of cells. KIR inhibitory receptors on the surface of NK cells (KIR2DL1, KIR2DL2 and KIR2DL3) can bind to MHC class I molecules and inhibit NK cell activation. In vitro experiments show that blocking KIR2DL1-3 with IPH2102 monoclonal antibody can increase the resistance of tumor activity. The clinical phase I-II studies of AML and MM have confirmed the safety of anti-KIR. Although anti-KIR alone has not shown significant antitumor effects, its combination with CTLA4 or PD1 inhibitors is worth looking forward to.

Immunotherapy is a major breakthrough in the field of cancer treatment in recent years. At present, this type of therapy focuses on the use of the adaptive immune system and has achieved great success in "using immune checkpoints to suppress the release of anti-tumor CD8 + T cell responses". However, there is growing evidence that some cancers can develop multiple strategies to evade the recognition of CD8 + T cells, and such tumors are preferentially attacked by natural killer cells (NK cells).

Unlike CD8 + T cells, NK cells are natural lymphocytes and can express receptors that recognize tumor cell and pathogen-infected cell surface ligands, such as NKG2D (NK group 2D) receptors. The NKG2D-NKG2D ligand axis (NKG2D–NKG2D ligand axis) is the main activation pathway for human NK cell-mediated recognition of tumor cells and virus-infected cells.

However, cunning tumors have also evolved mechanisms that escape NK cell surveillance and impair NK cell recognition. Among them, NKG2D ligands-MICA and MICB (which are produced by tumors and exposed on the tumor surface)-are a major mechanism for detachment from tumor cell surfaces. This escape has prevented the immune system from using MICA and MICB as a signal for an attack. Previously, studies have found shedding MICA and MICB in the serum of cancer patients, which is often associated with poor prognosis and impaired NK cell function.

Key antibody-mAb 7C6

So, is there a way to prevent proteins such as MICA and MICB from falling off the tumor surface, so that the immune system can play an anti-cancer effect? This is exactly what the team led by Professor Kai W. Wucherpfennig answered in the Science paper entitled "Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity".

In the study, scientists from institutions such as the Dana-Farber Cancer Institute and Harvard Medical School proposed an effective way to improve NK cell recognition of tumor cells, extending cancer immunotherapy beyond T cells.

Specifically, in order to prevent this immune escape and allow NK cells to effectively recognize tumors, scientists designed an antibody that targets MICA and MICB, mAb 7C6. In lung cancer and melanoma mice, mAb 7C6 not only increased the levels of MICA and MICB on the surface of cancer cells (this indicates that the tumor failed to "strip" these two proteins), but also increased the infiltration of natural killer cells in the tumor .

In mice with melanoma and lung metastases, mAb 7C6 treatment helped reduce tumor burden. At the same time, research also confirms that this anti-tumor immunity is mainly mediated by NK cell activation of NKG2D and CD16 Fc receptors.

NK cell immunotherapy

With the increase of age, the number and activity of NK cells gradually decreased. The activity of NK cells began to decline sharply at 40 years of age, and decreased to half of that at 60 years of age. Environmental pollution and mental stress would accelerate the decline of NK cell activities. This is why cancer is more common after the age of 50.

Japanese scientists have invented a multi-billion-fold multiplication method, which involves drawing 50 ml from human blood, separating a very small amount of NK cells, and then expanding and culturing them, increasing the number to 1000 times, and the number reaching 1 billion to 5 billion. A lot of NK cells will be circulated back to the body with blood 3,000 to 4,000 times throughout the body, killing cancer cells, aging cells, diseased cells, bacterial viruses, etc. in the body to achieve anti-cancer, anti-cancer, anti-aging, boost immunity, and decrease the risk of getting sick.

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