Natural Killer Cells in Immunotherapy: Are We Nearly There?

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.

The landscape of bispecific T cell engager in cancer treatment

“…Further studies are needed to evaluate whether the BiTE for the recruitment of γδ T cells is more effective than classical BiTE targeting CD3 that is expressed on both αβ and γδ T cells [172]. In addition to T cells, NK cells are also essential effector cells as a part of innate immunity that contribute to anti-tumor responses, therefore, considerable interest has recently focused on the potential of NK cells for cancer immunotherapies [173]. Bispecific killer cell engager (BiKE) that ligate CD16 on NK cells and a tumor antigen on tumor cells has been developed to activate NK cells and induce target cell lysis, to further improve activation, expansion, and survival of NK cells, a modified IL-15 crosslinker is infused into BiKE to create trispecific killer engager (TriKE) which has shown superior anti-tumor activity compared with BiKE [174,175] (Fig.…”

Tumor Secretome to Adoptive Cellular Immunotherapy: Reduce Me Before I Make You My Partner

“…The well-recognized anti-tumor activity of NK cells has led to many clinical studies administering either NK cells or CAR-modified NK cells, although results to date have shown mainly safety but not a high efficacy ( 18 ). These findings suggest the need to optimize NK cell anti-tumor efficacy.…”

“…In this regard, there are two main populations of NK cells in peripheral blood, the mature and cytotoxic NK with CD56 low CD16 high expression, which constitutes 90% of NK cells, and the immature and immunoregulatory NK cells characterized by CD56 high CD16 low/neg CD25 + expression, which comprise approximately 10% of peripheral blood (PB)-NK ( 18 , 19 ). A third transient population, known as decidual NK (dNK) cells, present at the fetal-maternal interface during the first months of pregnancy, representing 70% of immune cells in the decidua.…”

The Role of Chimeric Antigen Receptor-T Cell Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and Tribulations, and the Road Ahead

“…Other new areas of research in progress to improve the ability of CAR-T cells, resist the TME and decrease the immunogenicity [ 3 , 43 ] include (1) multitargeted CAR-T cell technologies; (2) Reforms in the manufacture of T cells (e.g., decrease the risks associated with using virus vectors, including DNA damage, and reduce cost and time of production: by replacing them with nonvirus-based technologies, such as Sleeping Beauty and PiggyBac transposition leading to the production of T cells with high persistence and low DNA damage [ 38 , 43 ], thus solving the various potential insertion-related mutations); (3) gene-editing techniques including the use of a nonintegrated lentiviral vector, recruiting CAR-T cells by oncolytic virus equipped with chemokine genes, generation of CAR-T cells with CRISPR/cas9 technology (clustered regularly interspaced short palindromic repeats/CRISPR- associated protein nine) and the use of CAR-NK (Natural killer) cells [ 2 , 44 ]. Apart from the above-mentioned technical aspects, one more area that one needs to address to make CAR therapy more accessible is the huge cost involved.…”