Allogeneic NK Cells — Anti-Leukemic Effects in Haploid Stem Cell Transplantation

Regardless of the chemotherapy or radiotherapy regimen used, many hematologic malignancies remain incurable with chemotherapy and radiotherapy alone. Allogeneic hematopoietic stem cell transplantation ( HSCT ) is the only curative option for a large number of blood cancers today. In allogeneic HSCT, the main goal is to replace the patient's immune system with the normal hematopoietic function of an allogeneic donor. The donor's immune system response to the recipient is called the transplant reaction. This response, referred to as GvL, which stands for graft versus leukemia/lymphoma, is able to eliminate residual malignant cells in patients and control hematologic malignancies over an extended period of time. The major setback to this theoretically ideal solution is a serious side effect: graft-versus-host disease ( GVHD ). The donor's immune system—essentially alloreactive T lymphocytes—attacks the host's healthy tissues ( especially the skin, digestive tract, liver, and lungs, but any organ may be affected ). To limit the risk of severe GVHD, most allogeneic HSCT is performed with an HLA-identical donor and therefore requires a complete HLA match between donor and recipient.

In this particular case, activation of haploid NK cells from the donor may be considered. In fact, certain class I HLA molecules ( =KIR ligands ) on the surface of recipient leukemia cells may not be recognized by inhibitory KIR receptors on donor NK cells. This phenomenon is called the GVL NK effect and is mediated by KIR/KIR ligand mismatch.

This concept has been reported in previous studies to exert antileukemic effects through such mismatches, particularly in patients transplanted with haploidentical donors in the AML setting [7,8] . However, this antileukemic effect of alloreactive NK cells after allogeneic HSCT is controversial, with some studies showing conflicting results. There is no doubt that NK cells, which possess significant plasticity, adapt to their environment or experience delayed maturation after transplantation, thereby reducing their potency and cytotoxicity [9,10] . Nonetheless, even though the in vivo role of NK cells is not as well documented as that of T cells, the development of haploidentical HSCT since the late 1990s has helped to elucidate this specific lymphocyte population and further exploit it with enormous potential. Anti-tumor cytotoxic potential [11,12] .