Engineered NK Cells Against Cancer and Their Potential Applications Beyond

Abstract

Cell therapy is an innovative therapeutic concept where viable cells are implanted, infused, or grafted into a patient to treat impaired or malignant tissues. The term was first introduced circa the 19th century and has since resulted in multiple breakthroughs in different fields of medicine, such as neurology, cardiology, and oncology. Lately, cell and gene therapy are merging to provide cell products with additional or enhanced properties. In this context, adoptive transfer of genetically modified cytotoxic lymphocytes has emerged as a novel treatment option for cancer patients. To this day, five cell therapy products have been FDA approved, four of which for CD19-positive malignancies and one for B-cell maturation antigen (BCMA)-positive malignancies. These are personalized immunotherapies where patient T cells are engineered to express chimeric antigen receptors (CARs) with the aim to redirect the cells against tumor-specific antigens. CAR-T cell therapies show impressive objective response rates in clinical trials that, in certain instances, may reach up to 80%. However, the life-threatening side effects associated with T cell toxicity and the manufacturing difficulties of developing personalized therapies hamper their widespread use. Recent literature suggests that Natural Killer (NK) cells, may provide a safer alternative and an ‘off-the-shelf’ treatment option thanks to their potent antitumor properties and relatively short lifespan. Here, we will discuss the potential of NK cells in CAR-based therapies focusing on the applications of CAR-NK cells in cancer therapy and beyond.

A bibliometric and scientific knowledge-map study of the chimeric antigen receptor (CAR) natural killer (NK) cell-related research from 2010 to 2022

“…CAR-NK cell therapy is a promising adoptive cell therapy (73). This study is the first time comprehensively and objectively analysing the CAR-NK cell field by combining bibliometrics with scientific knowledge maps.…”

IRF2 is required for development and functional maturation of human NK cells

“…Strategies for the development of NK cell based therapies currently focus on the source from which NK cells are derived and on enhancing NK cell potency and persistence ( 30 ). Several sources of NK cells are being investigated, including peripheral blood NK cells, NK cell lines and stem cell-derived NK cells ( 31 ). Stem cell-derived NK cells offer a promising resource as they provide the ability to manipulate the differentiation process and generate a standardized off-the-shelf therapy ( 31 ).…”

“…Several sources of NK cells are being investigated, including peripheral blood NK cells, NK cell lines and stem cell-derived NK cells ( 31 ). Stem cell-derived NK cells offer a promising resource as they provide the ability to manipulate the differentiation process and generate a standardized off-the-shelf therapy ( 31 ). In order to achieve the required numbers of NK cells with optimal immunoregulatory and cytotoxic functions, a more complete understanding of human NK cell differentiation and maturation is needed.…”

TXNIP Promotes Human NK Cell Development but Is Dispensable for NK Cell Functionality

“…The reduced concern for graft-versus-host disease and the possibility of off-the-shelf therapy makes NK cells an appealing candidate for clinical applications [ 32 ]. Currently, multiple clinical studies with NK cells for adoptive transfer are ongoing, using peripheral blood NK cells, NK cell lines, or stem cell-derived NK cells [ 33 ]. As NK cell-based therapy requires sufficient numbers of functional NK cells, an efficient ex vivo expansion period is essential.…”