**1. Introduction**

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is one of the most effective therapy for leukemia and other malignant diseases [1]. Its major complications are

graft-versus-host disease (GvHD), infections, and leukemia relapse [2, 3]. Natural killer (NK) cells represent a key component of innate lymphoid cells and provide defense against microbial infection and malignant transformation by direct cytotoxicity and cytokine production [4, 5]. The role of NK cells in allo-HSCT was first demonstrated in haploidentical transplants [6]. During T-cell depleted haploidentical HSCT, the rapid recovery of donorderived NK cells mediated potent graft-versus-leukemia (GvL) effect. Importantly, alloreactive NK cells mediated beneficial GvL effect without the occurrence of GvHD, which was consistently caused by donor T cells [7, 8].

Although the rapid reconstitution of donor NK cells plays a critical role in their GvL effect of the graft, they still take about 6 months or more to acquire maturation phenotype and full functionality [9]. This immaturity and insufficient education status may result in impaired function of donor NK cells in the early stage post transplantation. In addition, since the alloreactivity of donor NK cells was proved to account for the clinical benefit, genotyping the polymorphisms of killer cell immunoglobulin-like receptor (KIR), human leukocyte antigen (HLA) and Fcγ receptor (FcγR) are important for donor selection to maximize the GvL effect [10]. Sufficient numbers of allogeneic NK cells with high purity can also be generated and expanded through several sources including peripheral blood mononuclear cells, umbilical cord blood (UCB), and bone marrow–derived CD34<sup>+</sup> cells to be adoptively transferred after allo-HSCT [11, 12]. Many approaches involving the use of different feeder cells, engineered feeder cell, and cytokine stimulation were utilized to achieve sufficient numbers of donor NK cells with the most efficient GvL effect and clinical responses [13, 14]. Moreover, seven NK cell lines have been established to be used effectively during allo-HSCT, among which, NK-92 cell line has been shown to be safe and efficient in clinical trials [15–17]. Recently, genetic modification of NK cells has also been developed to enhance their function. Both gene transfer of chimeric antigen receptors (CARs) and expression of cytokine transgenes in NK cells are performed to improve the efficacy of NK cells therapy [18–20]. Furthermore, although traditionally considered as members of innate branch, increasing studies suggest that NK cells also "remember" prior certain stimulation like antigens, cytomegalovirus (CMV), or cytokines [21–26]. It draws particular interest to evaluate the role of adoptively transferred memory-like donor NK cells in allo-HSCT. Based on these research progresses of donor NK cell-mediated immunotherapy during allo-HSCT, in this chapter, we will describe the present state of donor NK cell therapy during allo-HSCT and its future direction aiming to improve therapeutic benefit of donor NK cells.
