Natural Killer Cells in Immunotherapy: Are We Nearly There?

SIMPLE SUMMARY: Here, we review the last pre-clinical and clinical studies published in the last five years where natural killer (NK) cells have been administered as an immunotherapy option for the treatment of cancer patients. We describe studies administering NK cells alone and in combination with monoclonal antibodies that either promote antibody-dependent cell cytotoxicity or block immune checkpoint receptors. We review the use of genetically modified NK cells including chimeric antigen receptor (CAR)-modified NK cells and other modifications that can enhance the anti-tumor activity of NK cells. Moreover, we describe studies related to the antimicrobial activity of NK cells as we believe they demonstrate important lessons that we can learn and apply to improve the anti-tumor activity of NK cells. All these studies are described with the aim to find tips to improve the success of NK cells as an immunotherapy option in cancer patients. ABSTRACT: Natural killer (NK) cells are potent anti-tumor and anti-microbial cells of our innate immune system. They are equipped with a vast array of receptors that recognize tumor cells and other pathogens. The innate immune activity of NK cells develops faster than the adaptive one performed by T cells, and studies suggest an important immunoregulatory role for each population against the other. The association, observed in acute myeloid leukemia patients receiving haploidentical killer-immunoglobulin-like-receptor-mismatched NK cells, with induction of complete remission was the determinant to begin an increasing number of clinical studies administering NK cells for the treatment of cancer patients. Unfortunately, even though transfused NK cells demonstrated safety, their observed efficacy was poor. In recent years, novel studies have emerged, combining NK cells with other immunotherapeutic agents, such as monoclonal antibodies, which might improve clinical efficacy. Moreover, genetically-modified NK cells aimed at arming NK cells with better efficacy and persistence have appeared as another option. Here, we review novel pre-clinical and clinical studies published in the last five years administering NK cells as a monotherapy and combined with other agents, and we also review chimeric antigen receptor-modified NK cells for the treatment of cancer patients. We then describe studies regarding the role of NK cells as anti-microbial effectors, as lessons that we could learn and apply in immunotherapy applications of NK cells; these studies highlight an important immunoregulatory role performed between T cells and NK cells that should be considered when designing immunotherapeutic strategies. Lastly, we highlight novel strategies that could be combined with NK cell immunotherapy to improve their targeting, activity, and persistence.