Many cancer therapies that have emerged in the past decade have been developed to increase anti-tumor immunity. Specifically, these therapies promote innate and adaptive immune responses and equip the body’s own immune system to work as a weapon against tumors.
Currently, most approaches have focused on enhancing T cell responses. One such approach targets inhibitory pathways in order to unleash cytotoxic immune effector cells, which is a key element of antitumor immune responses. Another approach targets activating pathways—such as with chimeric antigen receptor (CAR) T cells—and has been successful in treating non-solid tumors. However, CAR T cell therapy has been largely ineffective in treating solid tumors and also poses risky potential side-effects of CAR T cell therapy, such as graft-versus-host disease or toxic effects (i.e. systemic cytokine-release syndrome and CAR-T-cell-related encephalopathy syndrome).
A recent study reported promising results of another therapeutic method that showed stronger anti-tumor activity in vitro and in vivo in mouse models than that of gold standard monoclonal antibodies (mAbs) used in immunotherapies. Rather than manipulating effector T cells, Gauthier et al. (2019) focused their research on natural killer cell engagers (NKCEs) for cell therapies. Natural killer (NK) cells show high antitumor potential; in fact, there is a correlation between metastatic tumor growth and poor NK cell function in multiple types of solid tumors. In this study, researchers found that the natural cytotoxicity receptor NKp46 was frequently expressed on NK cells in many types of human solid cancers. Even more, when compared with NKG2D, another activating NK cell receptor, NKp46 outperformed by exhibiting more efficient lysis of tumor cells in vitro, suggesting that NKp46 may be a good candidate for therapeutic targeting.
Amazingly, they generated 14 different humanized mAbs with high affinity to different parts of the NKp46 extracellular domain. Even more, they created a trifunctional NKCE by combining a single-chain variable fragment (scFv) which binds to a tumor antigen (e.g. CD19), a monomeric Fc that binds to CD16, and an anti-NKp46 mAb which are both NK cell activating receptors that promote antibody-dependent cellular cytotoxicity (ADCC) (Figure 1). In vivo in mouse models, the trifunctional NKCE treatment not only induced tumor clearance, but also increased the NK cell count within the tumors, either via increased infiltration or intratumoral proliferation. The development of trifunctional NKCEs in this study led to the full activation of the NK cells which in turn drove stronger anti-tumor activities. For more on this exciting study, click here for the full paper.