NK Cell-Based Immunotherapies in Cancer

Abstract

With the development of technologies that can transform immune cells into therapeutic modalities, immunotherapy has remarkably changed the current paradigm of cancer treatment in recent years. NK cells are components of the innate immune system that act as key regulators and exhibit a potent tumor cytolytic function. Unlike T cells, NK cells exhibit tumor cytotoxicity by recognizing non-self, without deliberate immunization or activation. Currently, researchers have developed various approaches to improve the number and anti-tumor function of NK cells. These approaches include the use of cytokines and Abs to stimulate the efficacy of NK cell function, adoptive transfer of autologous or allogeneic ex vivo expanded NK cells, establishment of homogeneous NK cell lines using the NK cells of patients with cancer or healthy donors, derivation of NK cells from induced pluripotent stem cells (iPSCs), and modification of NK cells with cutting-edge genetic engineering technologies to generate chimeric Ag receptor (CAR)-NK cells. Such NK cell-based immunotherapies are currently reported as being promising anti-tumor strategies that have shown enhanced functional specificity in several clinical trials investigating malignant tumors. Here, we summarize the recent advances in NK cell-based cancer immunotherapies that have focused on providing improved function through the use of the latest genetic engineering technologies. We also discuss the different types of NK cells developed for cancer immunotherapy and present the clinical trials being conducted to test their safety and efficacy.

Keywords: Cancer; Immunotherapy; NK cells; Tumor microenvironment.

Figure 1. Methods of NK cell-based immunotherapy for cancer. Types of NK cells used for cancer immunotherapy. Allogeneic NK cells and autologous NK cells, manipulated with cytokines (IL-12, IL-15, and IL-18) and CAR, resulted in various types of NK cells for cancer immunotherapy. Somatic cells from the donor could be used as functional iPSC-based NK cells. Irradiated NK-92 cell line also served as an important resource for NK cell-based cancer therapy.

Figure 2. Schematic representation of human iPSC-based NK cell therapy. iPSCs are generated from somatic cells of the donor by reprogramming them using crucial various transcription factors, including Oct4, Sox2, c-Myc, and Klf4. The iPSCs are further differentiated into CD34⁺ cells and NK cells and can be expanded for clinical use.

Figure 3. Structure of CAR-NK cells. Design of CAR-NK cells. Three domains constitute the central part of the CAR structure (extracellular domain[s], a transmembrane domain, and intracellular domain[s]). The scFv region of the extracellular domain is composed of heavy and light chains. Components of the intracellular domain include CD3 signaling domain and co-stimulatory domains, such as CD28, 2B4, and CD137.