Immunotherapy with NK cells: recent developments in gene modification open up new avenues

Abstract

Chimeric antigen receptor (CAR)-T cell therapies have achieved remarkable success. However, application-related toxicities, such as cytokine release syndrome or neurotoxicity, moved natural killer (NK) cells into focus as novel players in immunotherapy. CAR-NK cells provide an advantageous dual killing-capacity by CAR-dependent and -independent mechanisms and induce few side effects. While the majority of trials still use CAR-T cells, CAR-NK cell trials are on the rise with 19 ongoing studies worldwide. This review illuminates the current state of research and clinical application of CAR-NK cells, as well as future developmental potential.

Keywords: CAR; NK cells; NK-92 cells; cell therapy.

Figure 1.

Receptor expression and interactions of (a) CD8⁺ T cells, (b) NK cells and (c) NK-92 cells with tumor target cells. T cells primarily recognize target cells via the TCR–HLA/MHC-I interaction, while NK and NK-92 cell activation depends on highly polymorphic activating and inhibitory germline-encoded receptors, such as KIRs or receptors of the NKG2-family. Activating receptors are shown in green, inhibitory receptors are shown in blue and killer receptors are shown in orange. Interleukin receptors are indicated in yellow, with the IL-2 receptor highlighted in orange on the NK-92 cell to illustrate its strong IL-2-dependency. Please note that only a selection of the most important receptors/ligands are shown, without claim of completeness.^–Abbreviations: CD, cluster of differentiation; DNAM-1, DNAX accessory molecule-1; HS, heparan sulfate; HLA, human leukocyte antigen; IL, interleukin; INF, interferon; KIR, killer-cell immunoglobulin-like receptor; MHC, major histocompatibility complex; MIC, MHC class I chain-related protein; NKG2, natural killer group 2; TCR, T cell receptor; TRAIL, TNF-related apoptosis-inducing ligand.

Figure 2.

Geographical distribution of ongoing NK cell (a) and CAR-NK cell (b) therapy trials worldwide, as registered by mid February 2020 at https://www.clinicaltrials.gov/ with “Cancer (NK AND cell) OR NK-92 OR (natural AND killer AND cell)” as search terms and CAR-NK cell clinical trials as listed in Table 1.