Genetically modified natural killer cells: an ‘off-the-shelf’ immunotherapy for cancer

The success of chimeric antigen receptor (CAR)-T cell-based immunotherapy is currently revolutionizing the treatment of hematological malignancies. However, there are numerous hurdles in developing this as an ‘off-the-shelf’ therapeutic for cancer treatment, including cost-of-goods, non-availability of allogeneic T cells, treatment induced toxicities, and disease relapse due to tumor antigen escape. Natural killer (NK) cells may provide a suitable platform to develop a safe ‘off-the-shelf’ cellular immunotherapy, while addressing many of the limitations of CAR-T cells. However, to elicit a successful clinical response using CAR-NK cells, a multi-factorial genetic engineering approach is necessary. In this review, we first discuss how NK cells are biologically different from T cells and summarize the different NK cell sources available for clinical application. Thereafter, based on our understanding of NK cell biology, we describe a list of critical genetic modifications, which in our opinion, are necessary to exploit the maximal therapeutic efficacy of genetically modified CAR-NK cells.

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