Adoptive NK cell therapy in AML: progress and challenges

Abstract

Adoptive cell therapy (ACT) using natural killer (NK) cells has emerged as a promising therapeutic strategy for acute myeloid leukemia (AML), addressing challenges such as chemotherapy resistance and high relapse rates. Over the years, clinical trials and studies have explored various sources of NK cells, including ex vivo expanded NK cell lines, CAR-NK cells, peripheral blood-derived NK cells, and umbilical cord blood-derived NK cells. These therapies have demonstrated varying degrees of therapeutic efficacy, ranging from transient anti-leukemia activity to sustained remission in select patient groups. Toxicity profiles have generally shown favorable safety outcomes, with minimal incidence of severe adverse effects such as cytokine release syndrome (CRS) or graft-versus-host disease (GVHD). However, persistent challenges remain, including limited NK cell persistence, relapse, and heterogeneity in patient responses. This review provides a comprehensive analysis of clinical outcomes and toxicity profiles provided from clinical trials, clinical studies and case reports conducted in the last 15 years to judge on the efficacy, safety and applicability of using NK cells for ACT of AML. Our review highlights the significant potential of NK cell-based therapies for AML, while addressing the technical and biological challenges that must be overcome to enhance their efficacy and safety.

Keywords: Acute myeloid leukemia (AML); Adoptive cell therapy (ACT); Graft versus host disease (GVHD); Graft versus leukemia (GVL); Hematopoietic stem cell transplantation (HSCT); NK cells.

Fig. 1

NK cell antitumor activity. NK cells have several functions where it secretes inflammatory cytokines as IFNγ and TNFα. It can perform apoptosis either by the secretion of granzymes and perforin or through FasL-FasR interaction. It has activating receptors that can bind to activating molecules expressed on tumor cells and activate NK cell function. It can also kill cancer cells by the help of IgG through ADCC. ADCC, antibody dependent cell mediated cytotoxicity; CD16, cluster of differentiation 16; FasL, Fas ligand; FasR, Fas receptor; MHC I, major histocompatibility complex class I; IFNγ, interferon gamma; TNFα, tumor necrosis factor alpha. Created in https://BioRender.com

Fig. 2

Mechanisms of evasion of NK cells by AML.AML cells can evade the NK cell activity through several mechanisms. This can be either due to defective NK cells with regards to their function or number of infiltrating NK cells. AML blasts also express immunosuppressive factors like GITRL and CD137L. These ligands bind to receptors that belong TNFR family which cause defective killing and decrease IFN-γ production by NK cells. CD200 is another immunosuppressive factor produced by AML blasts that caused lower expression of natural cytotoxicity receptors (NCRs) on NK cells and IFN-γ production. Lower levels of ETS-1 in NK cells of AML patients were also proven. ETS-1 is a transcription factor that binds to part of the promoter region of the NCR gene. Also, higher expression of inhibitory receptor CD94/NKG2A, that bind to HLA-E on AML cells inhibit NK cell function. AML, acute myeloid leukemia; CD200, cluster of differentiation 200; CD94, cluster of differentiation 94; CD137L, CD137 ligand; ETS-1, ETS Proto-Oncogene 1 Transcription Factor; GITRL, glucocorticoid-induced tumor necrosis factor receptor related protein ligand; KIR, kill inhibitory receptor; NK, natural killer cell; MHC I, major histocompatibility complex class I. Created in https://BioRender.com

Fig. 3

NK cells used for adoptive cell transfer include the use of NK-92 cell line which is expanded ex vivo. Also, genetically manipulated NK-92 cell lines were generated to express CD33 chimeric antigen receptor which were shown to have better cytotoxic effect on leukemic cells in vitro. Another source of NK cells is to prepare NK cells from CD34+ umbilical cord blood cells isolated from partially HLA matched umbilical cord blood. Isolation and expansion of NK cells from peripheral blood donors is also used. CD33, cluster of differentiation 33; CD34, cluster of differentiation 34; ML, memory like; NK, natural killer cell; IL, interleukin; rhIL, recombinant human interleukin; UC, umbilical cord; UCB, umbilical cord blood. Created in https://BioRender.com