Natural killer cell therapy for hematologic malignancies: successes, challenges, and the future

Abstract

The adoptive transfer of natural killer (NK) cells is an emerging therapy in the field of immuno-oncology. In the last 3 decades, NK cells have been utilized to harness the anti-tumor immune response in a wide range of malignancies, most notably with early evidence of efficacy in hematologic malignancies. NK cells are dysfunctional in patients with hematologic malignancies, and their number and function are further impaired by chemotherapy, radiation, and immunosuppressants used in initial therapy and hematopoietic stem cell transplantation. Restoring this innate immune deficit may lead to improved therapeutic outcomes. NK cell adoptive transfer has proven to be a safe in these settings, even in the setting of HLA mismatch, and a deeper understanding of NK cell biology and optimized expansion techniques have improved scalability and therapeutic efficacy. Here, we review the use of NK cell therapy in hematologic malignancies and discuss strategies to further improve the efficacy of NK cells against these diseases.

Keywords: Cellular therapy; Hematologic malignancy; Natural killer cells.

Fig. 1

Sources for expanded NK cells. Current NK cell therapies are derived from peripheral blood (PB) NK cells, umbilical cord/placental NK cells, NK cell lines, or induced pluripotent stem cells (iPSC). Isolated NK cells are expanded utilizing cytokine stimulation with or without the presence of feeder cells. Yellow lightning bolts indicate timepoints utilized for genetic alteration of the final expanded NK cell product

Fig. 2

Hypoxia. Hypoxia driven upregulation of CD73 leads to increased adenosine binding at the A2A receptor (A2AR). The A2AR inhibits NK cell function through the SOCS pathway via downregulation of activating receptors. Increased expression of the hypoxia inducible factor 1-alpha (HIF1α) in leukemic blasts results in upregulation of ADAM10 and subsequent cleavage of MIC-A—the canonical ligand for the NK cell activating receptor NKG2D

Fig. 3

Immune checkpoints. Binding of leukemic cell-secreted galectin-9 at TIM-3, PD-L1 at PD-1, or TIGIT ligand at the TIGIT receptor inhibits NK cell cytotoxicity. Similarly, tumor cell expression of MHC Class 1 molecules leads to NK cell tolerance through interaction with inhibitory KIRs. Blockade of these immune checkpoint pathways reverses NK cell dysfunction in the tumor microenvironment

Fig. 4

IDO. The intracellular enzyme Indoleamine 2,3-dioxygenase (IDO) catalyzes tryptophan to kynurenine, a ligand for the aryl hydrocarbon receptor (AHR). Upon kynurenine binding, AHR crosses the nuclear membrane and associates with the AHR nuclear translocator protein (ARNT). The AHR-ARNT complex binds to DNA promotor regions leading to differential expression of genes associated with immune tolerance of malignancy. In NK cells, AHR-ARNT activates transcription of miR-29b and inhibits NK cell maturation and function

Fig. 5

TGF-β. TGF-β secreted by leukemic blasts binds to the TGF-β receptor on NK cells leading to phosphorylation, trimerization, and translocation of SMAD complexes across the nuclear membrane. The downstream epigenetic modifications inhibit NK cell function with decreased cytokine production, impaired cytotoxicity, and downregulation of NK cell activating receptors (NKG2D, NKp30, DNAM-1, TRAIL, and CD16)

Fig. 6

NK cell therapy barriers and solutions. a Strategies to improve in vivo persistence of adoptive NK cells include use of lymphodepleting chemotherapy, repeated NK cell doses, exogenous cytokine stimulation, and cytokine secreting “armored” NK cells. b Tumor cell immune evasion can be overcome by antibodies directed at the tumor antigen to encourage NK cell ADCC, bispecific engagers interacting with NK activating receptors, or engineered chimeric antigen receptors. c Strategies to decrease immune evasion in the tumor microenvironment include (clockwise from the top left) genetic knock out/in of proteins to enhance NK function (ex. CD38 knock out), small molecule inhibitors or immunomodulatory drugs (ex. PARP inhibitors to upregulate NK activating receptors), priming the NK cells ex vivo for preservation of function in vivo (ex. TGFβ imprinting preserving cytolysis and cytokine secretion upon re-exposure to TGF β in the TME), and checkpoint blockade