Natural killer cells unleashed: Checkpoint receptor blockade and BiKE/TriKE utilization in NK-mediated anti-tumor immunotherapy

Abstract

Natural killer (NK) cells have long been known to mediate anti-tumor responses without prior sensitization or recognition of specific tumor antigens. However, the tumor microenvironment can suppress NK cell function resulting in tumor escape and disease progression. Despite recent advances in cytokine therapy and NK cell adoptive transfer, tumor expression of ligands to NK - expressed checkpoint receptors can still suppress NK mediated tumor lysis. This review will explore many of the checkpoint receptors tumors utilize to manipulate the NK cell response as well as some of the current and upcoming pharmacological solutions to limit tumor suppression of NK cell function. Furthermore, we will discuss the potential to use these drugs in combinational therapies with novel antibody reagents such as bi- and tri-specific killer engagers (BiKEs and TriKEs) against tumor-specific antigens to enhance NK cell-mediated tumor rejection.

Keywords: BiKE; CTLA-4; Checkpoint; Immunotherapy; Natural killer cells; PD-1; TriKE.

Figure 1. Activating and inhibitory receptor interactions between natural killer cells and tumor targets

NK cell responses to tumor targets are regulated by a delicate balance of activating and inhibitory signals provided by the receptors depicted. NK activating and inhibitory receptor expression varies based on NK cell subset as well as cytokines and soluble ligands present at or near the tumor microenvironment. Ligands present on tumor cells also vary depending on tumor type and conditions in the microenvironment.

Figure 2. Design and function of tumor antigen-specific bi- and tri-specific killer engagers (BiKEs and TriKEs)

A) Schema of the basic design and structure of a BiKE consisting of an anti-CD16 scFV linked to an scFv specific to a tumor-expressed antigen or B) a TriKE of the same design including the cytokine, IL-15, included as a linker between the two scFv components. C) Proposed function of tumor antigen-specific BiKE and TriKE.