Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

Abstract

The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

Expanded and activated allogeneic NK cells are cytotoxic against B-chronic lymphocytic leukemia (B-CLL) cells with sporadic cases of resistance

“…This approach, however, is more expensive and has secondary effects. NK cells, in view of their low toxicity 5 , will probably have fewer undesirable effects. The sporadic resistance observed initially in one patient did not correlate with match between the KIR ligands expressed by eNK cells and HLA-I expressed by leukemic cells.…”

“…This approach, however, is more expensive and has secondary effects. NK cells, in view of their low toxicity 5 , will probably have fewer undesirable effects.…”

“…Although they differ in antigen specificity, NK cells and CTLs share the same effector mechanisms to efficiently kill tumor cells: perforin-mediated granzyme B delivery inside target cells and death ligand-induced apoptosis, namely FasL and TRAIL 4 . Therefore, advances in the understanding of NK cell biology and function make them a powerful tool for new immunotherapies 5 , some of which are currently in clinical trials 6 .…”

Contribution of NK cells to HBsAg seroconversion in inactive HBsAg carriers following pegylated IFN therapy

“… 14 Aside from the strong cytotoxic activity against tumour cells and viruses, NK cells secrete a variety of cytokines (IFN-γ, TNF-α, GM-CSF and chemokines), participate early in the innate immune response, modulate the acquired immune response and act as a bridge linking the two immune responses. 15 – 17 Here, we first performed longitudinal analysis of lymphocyte subsets in IHCs undergoing PEG-IFN treatment, focusing on NK cells.…”

Dissecting the NK Cell Population in Hematological Cancers Confirms the Presence of Tumor Cells and Their Impact on NK Population Function

“…The impact of disease in NK subsets is not exclusive of cancer. Other diseases including infection and autoimmunity induce impaired NK function and the emergence of NK subsets rarely observed in healthy individuals [8]. However, little is known about the fate of the disease-specific subsets.…”