Clinical utility of natural killer cells in cancer therapy and transplantation

Abstract

Natural killer (NK) cells recognize deranged cells that display stress receptors or loss of major histocompatibility complex (MHC) class I. During development, NK cells become "licensed" only after they encounter cognate human leukocyte antigen (HLA) class I, leading to the acquisition of effector function. NK cells can be exploited for cancer therapy in several ways. These include targeting with monoclonal antibodies alone or combined with ex vivo and in vivo NK cell activation to facilitate adoptive immunotherapy using donor-derived NK cell products to induce graft-vs-tumor effects. In the adoptive transfer setting, persistence and in vivo expansion requires lymphodepleting chemotherapy to prevent rejection and provide homeostatic cytokines (such as IL-15) that activate NK cells. IL-15 has the advantage of avoiding regulatory T-cell expansion. Clinical applications are currently being tested. To enhance in vivo expansion, IL-2 has been used at low doses. However, low dose administration also leads to the stimulation of regulatory T cells. Monoclonal antibodies and bispecific killer engagers (BiKEs) may enhance specificity by targeting CD16 on NK cells to tumor antigens. Inhibition of CD16 shedding may also promote enhanced cytotoxicity. Future strategies include exploiting favorable donor immunogenetics or ex vivo expansion of NK cells from blood, progenitors, or pluripotent cells. Comparative clinical trials are needed to test these approaches.

Keywords: Acute myeloid leukemia; Adoptive cell therapy; Immunomodulation; Immunotherapy; NK cells.

Figure 1. Schema for NK cell manipulation in HCT and immunotherapy

Autologous or allogeneic NK cells can be collected from peripheral blood. Those cells can be enriched and infused or expanded with cytokines ± aAPCs prior to infusion into patients. Alternative sources of allogeneic NK cells include NK cell lines or NK cells derived from pluripotent stem cells. These NK cells can be further modified with chimeric antigen receptors specific for a patient’s tumor. In hematopoietic stem cell transplant (HSCT), NK cells can be transferred with the graft or develop from hematopoietic stem cells (HSCs). These alloreactive cells express inhibitory KIR and effector molecules that allow clearance of leukemic cells such as AML. If the patient reactivates CMV, a clonal expansion of NKG2C⁺CD57⁺KIR⁺ NK cells occurs, which have enhanced activity against AML cells. Finally, NK cells can be manipulated in vivo. These modalities include monoclonal antibodies to block inhibitory KIR or stimulation of ADCC through crosslinking of CD16. CD16 can also be stimulated by using bi- or tri-specific antibodies. ADCC can further be enhanced by blocking ADAM17 activity. To further enhance NK cell expansion and activity, Tregs and myeloid derived suppressor cells (MDSCs) must be eliminated.