Exploring the NK cell platform for cancer immunotherapy

Abstract

Natural killer (NK) cells are cytotoxic lymphocytes of the innate immune system that are capable of killing virally infected and/or cancerous cells. Nearly 20 years ago, NK cell-mediated immunotherapy emerged as a safe and effective treatment approach for patients with advanced-stage leukaemia. Subsequently, the field of NK cell-based cancer therapy has grown exponentially and currently constitutes a major area of immunotherapy innovation. In general, the development of NK cell-directed therapies has two main focal points: optimizing the source of therapeutic NK cells for adoptive transfer and enhancing NK cell cytotoxicity and persistence in vivo. A wide variety of sources of therapeutic NK cells are currently being tested clinically, including haploidentical NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, NK cell lines, adaptive NK cells, cytokine-induced memory-like NK cells and chimeric antigen receptor NK cells. A plethora of methods to augment the cytotoxicity and longevity of NK cells are also under clinical investigation, including cytokine-based agents, NK cell-engager molecules and immune-checkpoint inhibitors. In this Review, we highlight the variety of ways in which diverse NK cell products and their auxiliary therapeutics are being leveraged to target human cancers. We also identify future avenues for NK cell therapy research.

Fig. 1 ∣. NK cells respond to virally infected and transformed cells via balancing signals.

Natural killer (NK) cells express a variety of receptors with activatory or inhibitory functions (or both), and the balance of signalling inputs through these receptors dictates tolerance of or activation of cytotoxicity against the target cells. a ∣ When the overall level of inhibitory receptor signalling outweighs activating receptor signalling, NK cell activation is thwarted, resulting in tolerance of the signal-inducing cell. b ∣ Upon viral infection or transformation, cells typically upregulate stimulatory ligands for NK cell activating receptors such as NKG2D, with the resultant interactions inducing a level of activatory signalling that surpasses that of constitutive signalling through inhibitory receptors (such as killer immunoglobulin-like receptors (KIRs) and NKG2A), which activates NK cell cytokine release and cytotoxicity against the target cell. This scenario is referred to as the ‘induced-self’ response. c ∣ When class I MHC ligands of NK cell inhibitory receptors are downregulated, which commonly occurs in tumour cells, the loss of inhibitory signals and the resulting unabated positive signalling also leads to NK cell activation. This phenomenon is referred to as the ‘missing-self’ response.

Fig. 2 ∣. Summary of the various approaches to enhancing NK cell effector function.

From top right, clockwise: pro-inflammatory cytokines such as IL-12 and IL-18 enhance NK cell effector function and cytokine secretion, whereas anti-inflammatory cytokines such as IL-37 and TGFβ suppress NK cell function. IL-15 is a crucial homeostatic cytokine for NK cells; cytokine-inducible SH2-containing protein (CIS) is a negative regulator of IL-15 signalling and thus a potential therapeutic target. Recombinant IL-15 (rIL-15) and the IL-15 superagonist N-803 promote NK cell proliferation and persistence within the tumour microenvironment. NK cell engagers (for example, tri-specific killer cell engagers (TriKEs) that also include an IL-15 domain to enhance NK cell activation) and monoclonal antibodies (mAbs) capable of binding to and activating CD16 (low-affinity IgG Fc region receptor III) on NK cells enable the targeting of these cells towards tumour cells expressing specific antigens, such as CD19. Disintegrin and metalloproteinase domain-containing protein 17 (ADAM17) inhibitors reduce CD16 cleavage from the cell surface and might, therefore, enhance NK cell activity. Genetically modified cell products, such as chimeric antigen receptor (CAR) NK cells or NK cells with modified forms of CD16 (for example, FT-516), are also being investigated as a means of improving the antitumour activity of adoptive NK cell therapies. Moreover, GSK3 inhibition and cytomegalovirus (CMV) infection give rise to hyperfunctional NKG2C⁺CD57⁺ adaptive NK cells, which have been associated with favourable clinical outcomes. Knockout of CD38 in adoptively transferred NK cells can prevent antibody-dependent cell-mediated cytotoxicity (ADCC)-related fratricide during treatment with mAbs targeting this protein, such as daratumumab. Immune- checkpoint inhibitors could potentially relieve suppression of NK cell- mediated cytotoxicity by preventing inhibitory signalling through PD-1, NKG2A and killer immunoglobulin-like receptors (KIRs). Ultimately, signalling induced by Fas ligand (FASL) and TNF-related apoptosis-inducing ligand (TRAIL) on NK cells can trigger apoptosis of target cells. In addition, activation of members of the natural cytotoxicity receptor family, such as NKp46 and NKG2D, results in the release of preformed cytolytic granules containing granzyme B and perforin. NK cells also secrete chemokines that attract multiple subsets of immune cells with potential antitumour functions.