A Look under the Hood of the Engineered Human Natural Killer Cells

Abstract

Notwithstanding multimodal approaches including chemotherapeutic agents and radiation have been used for decades as major strategies to successfully treat cancer patients; however, the emergence of drug or radiation resistance led to a significant incidence of tumor relapse and hence limits their effectiveness. Therefore, the need for novel and effective strategies which are clinically vital; not only for improved efficacy to eliminate resistant tumor cells but also to permit less-toxic doses and potentially overcome resistance, was and still a hopeful goal. Natural killer (NK) cells comprise 5–10% of peripheral blood lymphocytes (PBLs). Owing to the fact that NK cells have an importance role in anti-tumour immunity as demonstrated by several elegant studies, therefore, this NK-cell activity has been exploited as the basis of cancer immunotherapy strategies. Nevertheless, tumor cells can effectively escape NK cell-mediated apoptosis through a cocktail of different mechanisms. Thus, to enhance NK cell effector function against tumors, different approaches have been recently developed to achieve an ex vivo NK-cell enhancement. One adoptive transfer approach uses expanded allogeneic NK cells, which are MHC class I-resistant. A second approach uses stable allogeneic NK cell lines, which is more practical for large-scale production and safety. A third approach is the genetic modification of NK cells or NK cell lines to highly express cytokines, Fc receptors and/or chimeric tumor-antigen receptors. Therapeutic NK cells can be derived from different sources, including peripheral or cord blood cells, stem cells or induced pluripotent stem cells (iPSCs). Here, we summarize the recent developments in genetic engineering of NK-cell-based biopharmaceuticals, and covering the usefulness, effectiveness, and safety for their clinical applications.