Natural Killer T (NKT) Cells
Natural Killer T (NKT) cells are unique T cells that combine the characteristics of NK cells. NKT cells were first discovered in 1986 by Dr. Masaru Taniguchi (currently visiting research supervisor, RIKEN, National Research and Development Agency ) and are known as the fourth lymphocytes following T cells, B cells, and NK cells. NKT cells account for around half of the T cells found in the liver and in bone marrow.
NKT cells are activated by recognizing the glycolipid antigens, producing many varieties of cytokines and inducing reactions of both immunoagitation and immunosuppression. Currently, studies on the structure-activity relationship that selectively induce an immune response using various glycolipid antigens are being actively conducted. A big feature of NKT cells is that they have little diversity because only one type of T-cell receptor (TCR) is manifested. Furthermore, while the T-cell receptor of regular T cells recognizes peptides presented in major histocompatibility complex (MHC molecules) as antigens, the T-cell receptor of NKT cells is unique in that it recognizes glycolipids presented in CD1d molecules as antigens as well, complementing recognition range of the antigen with T cells.
Anti-tumor effects of NKT cells
Effector function of directly attacking on tumor cells
Since NKT cells have the characteristics of NK cells which is the one of the natural immune cells, they have effector function of directly killing tumor cells. However, as the number of NKT cells in vivo is very small, the effects of direct cytotoxic activity are limited.
Activation of immune system by adjuvant effect
NKT cells produce large amount of interferon-γ (IFN-γ), a type of cytokine, to present adjuvant action that activates other immune cells, such as NK cells in the natural immunity system and killer T cells in the acquired immunity system, forming long-term immunologic memories.
Mechanisms of NKT cell-targeted therapy
NKT cell-targeted cancer immunotherapy
NKT cell-targeted cancer immunotherapy is a treatment method that targets the cancer patient's own NKT cells with the aim of activating them.
Antigen presenting cells (APCs) are separated from the patient's own peripheral blood and give an intravenous injection to the patients with their own cell formulation (such as regenerative machine) from the NKT ligand and pulse cultivation at the cell processing facility. Research and development of other cell formulations produced by inducing antigen-presenting cells such as iPS cells and by pulse cultivation of NKT ligands are also underway.)
Mechanisms of NKT cell-targeted cancer immunotherapy
When APCs presenting NKT ligands are administered to patients, NKT cells within the patient’s body recognize the ligands, and produce large quantities of cytokines such as interferon-γ (IFN-γ), resulting in activation of other cancer immune cell colonies (adjuvant effects)
1. It activates effector cell colonies, such as NK cells in the natural immunity system and CD8T cells (killer T cells) in the acquired immunity system, to attack cancer cells.
2. Some of the other immune cells (memory T cells, such as central memory and effector memory) that are strongly activated by NKT cells remain in the body and continuously attack cancer cells by forming long-term immunologic memories.
3. It acts on immature dendritic cells to promote maturity, thus restoring the immune function of cancer patients who are immunodeficient.
Advantages of NKT cell-targeted cancer immunotherapy
This immunotherapy does not target cancer cells themselves, but instead activates NKT cells which function as controller of the immune system. Notable anti-tumor effects have been shown as a result of the adjuvant effects of the activated NKT cells. The advantages of NKT cell-targeted cancer immunotherapy are introduced below.
1.Efficacy of NKT cell-targeted cancer immunotherapy is always expected to be effective irrespective of cancer types
NKT cell-targeted cancer immunotherapy does not target cancer cells themselves, but instead activates the patient's own immune function through the adjuvant effects of the IFN-γ produced by NKT cells, and is therefore expected to be effective irrespective of cancer types.
2.Efficacy of NKT cell-targeted cancer immunotherapy is always expected to be effective in any types of patients
NKT cells have antigen-receptors that are common to all humans, and recognize glycolipid combined with the CD1d molecule, which is only one of the races. Therefore, it can be expected to be effective in all types of patients, not restricted to HLA types, which are different in each patient.
3.NKT cell-targeted cancer immunotherapy simultaneously attacks various types of cancer cells
All types of cancer include 2 types of cancer cells that do and do not manifest tumor antigens. Existing cancer cell immunotherapy attacks either cancer cell, but this immunotherapy uses interferon-γ (IFN-γ) produced by NKT cells to simultaneously activate natural immunity systems such as NK cells and acquired immunity systems such as killer T cells (adjuvant effects) to attack and kill both types of cancer cells. In addition, since the effects are not restricted by tumor antigens, anti-cancer effects can be expected against newly emerging mutant cancer cells.
4.NKT cell-targeted cancer immunotherapy forms long-term immunologic memory
Some of the immune cells (memory T cells, such as central memory and effector memory) that are strongly activated by the adjuvant effects of IFN-γ produced by NKT cells remain in the body and form long-term immunologic memories.
5.NKT cell-targeted cancer immunotherapy improves immunodeficiency in cancer conditions
NKT cells are the only immune cells that can functionally respond to immature dendritic cells. Therefore, it is possible to reactivate the immune system, which is suffering from immunodeficiency due to suppression of dendritic cell maturation by cancer
Clinical data on NKT cell-targeted cancer immunotherapy
Clinical research on NKT cell-targeted cancer immunotherapy using α-galactosylceramide-pulsed dendritic cells (DCs)* was carried out at Chiba University Hospital in the 2000s. The subjects were 17 patients (Stage Ⅲb · Ⅳ) with advanced non-small cell lung cancer that showed resistance to surgery, radiation therapy, and anticancer therapy. The median survival time with the initial treatment only was approximately 18.6 months, which was more than four times that of the 4.6 months with best supportive care.
Interferon-γ (IFN-γ) production as an index of NKT cell activation was shown in approximately 90% of patients who participated in this clinical trial. However, when reviewing the survival rate by stratifying patients with two or more increases in the number of IFN-γ-producing cells and those who did not, It has been found to have a statistically significant correlation with prolonged survival time.
Of the 17 subjects treated using α-galactosylceramide-pulsed DCs, 10 subjects (approximately 60%) showed increases in IFNγ-producing cell counts to at least twice the levels before treatment, and the median survival time of these subjects was 31.9 months, which represented a marked increase. Since obtaining the results of this clinical trial, NKT cell-targeted cancer immunotherapy has been authorized as Advanced Medical Care B by MHLW for advanced lung cancer in 2011 and for lung cancer after surgery in 2014.
Reference can be made to http://www.mhlw.go.jp/topics/bukyoku/isei/sensiniryo/kikan03.html *: The novel product which AMBICION develops under the Pharmaceuticals and Medical Devices Law is "RK-pulsed APCs", and the ligands and APCs used in cell formulations and cultivation conditions are different from those used with αgalactosylceramide-pulsed DCs.
Clinical effects of NKT cell-targeted cancer immunotherapy for advanced lung cancer