Problems with NKT Cell Therapy
NKT cells are cells that exist in very small numbers in the body. Normally, less than 0.1% of T cells in the blood are NKT cells, making it difficult to collect a sufficient number of them. Therefore, it is necessary to proliferate them in large quantities outside the body, but the small number of NKT cells obtained initially is a major constraint. In addition, NKT cells may proliferate more slowly in culture than general T cells. Slow proliferation means that it takes time to secure the number of cells necessary for treatment, making efficient culture difficult. Long-term culture of NKT cells can lead to the loss of their characteristics and functions. In particular, a weakening of NKT cells’ specific antigen recognition ability and immunomodulatory function increases the risk of reduced therapeutic efficacy. Attempts have been made to differentiate and propagate iPS cells into NKT cells to address this problem, but because allogeneic iPS cells are used, there are legal restrictions at present, and clinical trials are limited to a few facilities. Therefore, a different approach has been devised: training NKT cells from within the body by having dendritic cells present antigens.

NKT Cell Targeted Therapy
Monocytes (dendritic cell progenitor cells) are collected from the patient’s blood via apheresis and cultured in vitro to form dendritic cells. Then, the glycolipid “α-galactosylceramide (α-GalCer)” is bound to the CD1d molecule of the dendritic cells to create an “α-GalCer-presenting dendritic cell (α-GalCer-DC) complex,” which is then returned to the body via intravenous infusion. When NKT cells recognize this complex with a receptor called the invariant T cell receptor, they are activated en masse, releasing large amounts of the cytokine interferon-γ, which primarily calls upon NK cells (innate immunity) and killer T cells (CD8+ T cells) (adaptive immunity) to powerfully attack cancer cells. Activated NKT cells also attack cancer cells, but their direct cytotoxic activity is limited due to the small amount present in the body. Furthermore, some activated immune cells become memory cells (such as memory T cells) and remain in the body, forming long-term immune memory and preventing cancer recurrence and metastasis. In addition, they mature dendritic cells whose function has been impaired by cancer, improving the immunosuppressed state.

The main difference between NK cells and NKT cells is that NK cells belong to innate immunity and directly attack cancer cells and other pathogens in an MHC-independent manner, while NKT cells possess the properties of both T cells and NK cells, recognizing lipid antigens via MHC molecules (CD1d) and performing both potent immunomodulation (cytokine production) and direct attack. The differences are shown in the table below.

Difference between NK cell and NKT cell therapy