Importance study effect natural killer (NK) cell therapy, hematopoietic stem cell transplantation for leukemia
Importance study effect natural killer (NK) cell therapy, hematopoietic stem cell transplantation for leukemia
Niloofar torkzadeh,1,*Mozhgan shirazi,2
1. Department of Biochemistry, Islamic Azad University, Falavarjan, Iran 2. Department of Biology, Scince and Reserch Branch, Islamic Azad, university, tehran, iran
Introduction: Natural killer (NK) cells belong to innate lymphoid immune cells that contribute to antitumor responses without prior sensitization. Dealing to the currently applied innate lymphoid cell nomenclature, NK cells are a prototypical member of the group 1 innate lymphoid cells insofar as they produce interferon g(IFN_γ) and developmentally require the common cytokine receptor g chain the transcriptional repressor inhibitor of DNA binding 2, and t bet. Allogeneic hematopoietic stem cell transplantation (HSCT) transplantation has a major role in the treatment of leukemia and hematological disease often the only treatment providing a change of cure in other wise refractory diseases. The primary approaches involved total body irradiation (TBI) or cyclophosphamide (CY).
Methods: we reviewed about 22 articles were conducted from 2019 to 2023 in the world and Iran. We searched some key words such as natural killer, stem cell, hematopoietic, leukemia, acute amyloid leukemia in ScienceDirect, Elsevier, PubMed and SID.
Results: NK cells use different innated receptors to sense their environment and respond to alterations induced by infections or by malignant cells transformation. In a process termed licensing NK cells use iKIRs for self-major histocompatibility complex (MHC) class Ι molecules to maintain a state of responsiveness and to kill target cells have lost MHC class Ι. Human NK cells comprise two main phenotypes based on the CD56 and CD16 markers. The CD56dim CD16+NK subset has great cytotoxic potential and is predominant in blood, whereas the CD56high CD16- subset produces abundant cytokines and is more abundant in lymph nodes. The functionality of NK cells is mediated and controlled by the balance between the expression of activating are inhibitory receptors. The main activating receptors are natural cytotoxic receptors (NCR, NKP30, NKP46, NKP44) NKG2D and DNAM-1 whereas the killer immunoglobulin like receptor (KIR) family and NKG2A are inhibitory receptors. In a high percentage of AML patient, the expression levels of some activating receptors (NKG2D, NKP30, NKP46, DNAM-1) are null or very low. Fauriat et all, reported that the NKP30 and NKP46 expression is reduced in AML patients at diagnosis but is partially recovered after CR and decreases again in an episode of disease relapse. It is also clear established that high levels of expression of NKP30 and NKP46 are associated with higher rates of overall relapse free and progression free survival compared with patient with reduced expression of their receptors. One benefit of this therapy is the low incidence of graft versus host disease (GVHD) and the production of a strong graft versus leukemia (GVL) that is associated with better survival and lower probability of relapse. Ex vivo stimulation of NK with a cytokine cocktail of IL12, IL15 and IL18 is an established alternative to avoid the in vivo administration of IL2 after NK cell infusion. These cells known as CIML (cytokine induced memory like) proliferate and produce high levels of IFN_γ during the first week after which its production decreases. Relapse of residual disease is a common cause of reduced survival following HSCT. This occurs in 20_70% of patients and is dependent on several factors including pre transplant disease status, cytogenetic subtypes (in acute myeloid leukemia (AML)) and in acute lymphoid leukemia (ALL), stem cell source, age of the patient and donor and type of conditioning regimen. In addition, relapse contributes to 40-45% of deaths following HLA matched identical HSCT and 34% in unrelated donor HSCT. The use of reduced intensity conditioning regimens has also led to GVL effects, which have been most marked in chronic myeloid leukemia (CML) and are also detectable myelodysplastic syndrome (MDS), AML and ALL.
Conclusion: NK cells and established NK cell lines such as NK92 can also be redirected towards target antigens expressed on leukemia blasts by chimeric antigen receptors (CARs). It has been shown that CAR_NK cells can overcome inhibitory signals and induce specificity killing of leukemia cells. In CML long term remissions can readily be obtained by the treatment with low dose IFN_γ and DLI, in AML long term remission may be obtained by a more aggressive approach involving mobilized stem cells and GM_CSF following cytarabine of repeated treatments with targeted drugs like azacytidine, sorafenib, midostaurin, immune modulatory, blast modulatory kit and DLI.