Natural killer cells are increasingly recognised as an attractive source of allogeneic immune effector cells in cancer immunotherapy. Over the past decade, several adoptive transfer trials using allogeneic NK cells from different sources have shown safety with little evidence of toxicities such as graft-versus-host disease, cytokine release syndrome or neurotoxicity that are often seen in T cell therapy. While clinical effects have been observed, improvements are warranted to increase relapse free survival and potentially cure cancer patients. Genetic engineering shows great potential for improving NK cell therapy through chimeric antigen receptors or knocking out immune checkpoints and MHC-I. Especially stem cell-derived natural killer cells are an ideal template as they can be cultured without T and B cell contamination and are relatively easy to genetically engineer compared to mature NK cells. Next to improving anti-tumour specificity, persistence can be improved by including cytokine domains in the chimeric antigen receptor, which is a great benefit over NK cell lines that need to be lethally irradiated to prevent uncontrolled proliferation. Importantly, the safety profile of adoptive NK cell transfer allows for minimal matching, which opens the door for large-scale production and cryopreservation to create an off-the-shelf therapy.

(BELG J HEMATOL 2020;12(2):59-65)