Killers 2.0: NK cell therapies at the forefront of cancer control

Abstract

Natural killer (NK) cells are innate cytotoxic lymphocytes involved in the surveillance and elimination of cancer. As we have learned more and more about the mechanisms NK cells employ to recognize and eliminate tumor cells, and how, in turn, cancer evades NK cell responses, we have gained a clear appreciation that NK cells can be harnessed in cancer immunotherapy. Here, we review the evidence for NK cells' critical role in combating transformed and malignant cells, and how cancer immunotherapies potentiate NK cell responses for therapeutic purposes. We highlight cutting-edge immunotherapeutic strategies in preclinical and clinical development such as adoptive NK cell transfer, chimeric antigen receptor-expressing NK cells (CAR-NKs), bispecific and trispecific killer cell engagers (BiKEs and TriKEs), checkpoint blockade, and oncolytic virotherapy. Further, we describe the challenges that NK cells face (e.g., postsurgical dysfunction) that must be overcome by these therapeutic modalities to achieve cancer clearance.

Figure 1. The NK cell armament of cancer immunotherapy: how to harness NK cells against cancer.

NK cells kill and eliminate cancer cells, but in the tumor microenvironment they are often insufficiently active or inhibited by immunosuppressive ligands and cytokines. To overcome this, a number of strategies have been developed to enhance NK cell activity against cancer in these settings: (A) Chemo- and radiotherapy induce immunogenic cell death of cancers, leading to expression of NKG2D ligands, HMGB1, and other DAMPs that drive NK cell activation. (B) Surgery leads to the development of an immunosuppressive microenvironment, in part through the expansion of MDSCs and the release of inhibitory cytokines such as TGF-β. PDE5 inhibitors alongside viral vaccines have proven to be highly effective in reversing this dysfunction. (C) Oncolytic viruses (OVs) infect and lyse cancer cells, but can also infect DCs, leading to their maturation and driving DC-NK cross talk and subsequent NK activation. OVs can also be engineered to deliver cytokines and other immune stimulants to the microenvironment to activate the immune system. (D) Engineered cytokines such as ALT-803, an alternate form of IL-15, have increased potency compared with conventional cytokines. (E) Checkpoint blockers such as anti–PD-1/PD-L1 and anti-TIGIT relinquish NK cells from the immunosuppressive effects exerted by tumors, allowing them to perform their cytolytic functions. (F) NK cells from autologous or allogeneic sources can be safely used as adoptive cell therapy. (G) The use of CARs enhances the efficacy of adoptive therapy. In particular, CARs expressing NKG2D with the CD3ζ and DAP10 intracellular signaling motifs drive potent antitumor immune responses. (H) BiKEs and TriKEs bring NK cells spatially closer to their targets and activate them. The TriKE 161533 contains a CD16-targeting motif for NK cells, a CD33-targeting motif for cancer cells and MDSCs, and an IL-15 linker to activate NK cells.