Natural killer cells in adoptive cell therapy: current landscape of genetic engineering strategies

Among adoptive cell-based immunotherapies, chimeric antigen receptor (CAR) therapy has shown promising results in cancer treatment. Treatment with CAR-T cells has produced remarkable clinical responses, especially in cases of relapsed and refractory leukemia and lymphoma. However, CAR-T cell therapy still presents several limitations, including some safety concerns related to neurotoxicity and aggressive inflammatory responses. As an alternative to T-cells, natural killer (NK) cells have been developed as an attractive option for efficient cancer immunotherapy. As they do not express T cell receptor (TCR), NK cell-based therapies are not associated with cytokine release syndrome (CRS) or graft versus host disease (GvHD), which enables a safer therapy and the ability to generate an allogeneic "off-the-shelf" product. Despite the innate cytotoxic activity of NK cells against malignant cells, the therapeutic application of unmodified NK cells has been compromised by the inhibitory tumor microenvironment (TME), which is responsible for poor cell expansion, inactivation, insufficient tumor infiltration, and limited in vivo persistence, leading to the dysfunction of NK cells after infusion. Advances in the genetic modification of NK cells can address some of these limitations and improve their therapeutic efficacy. In this review, we describe the advances in the development of engineered NK cells for cancer immunotherapy. As such, we provide an overview of recent viral and non-viral approaches for the genetic modification of NK cells. We also discuss their current clinical status in the field of immunotherapy, and their use in other clinical applications.