Gene-edited and CAR-NK cells: Opportunities and challenges with engineering of NK cells for immunotherapy

Treatment of many cancers, particularly those that remain difficult to treat or are refractive after standard-of-care therapies, has been challenging with cell-based therapies. Although relatively safe as allogeneic therapies and innately effective against cancers without the need for antigen sensitization, natural killer (NK) cells have necessitated use of genetic manipulation approaches to enhance their specificity, persistence, and homing. Chimeric antigen receptor (CAR) and gene-edited NK cell therapies have emerged as a potent treatment modality, addressing many of the issues that have plagued such gene-based therapies with other cell types. Early examples of engineered NK cell therapies have largely leveraged their activity against hematological malignancies in combination with conventional construct architectures or by editing putative genetic targets of immunosuppression. As the motivation to tackle more complex solid tumors grows, so has the sophistication and emergence of NK-specific constructs and engineering approaches. Multi-CARs, combinations with diverse genome editing technologies, as well as responsive and sensing CARs have appeared in the context of NK cell therapy. Here we discuss engineering approaches for NK cell therapy, the latest developments in the field, and what stands in the way of those promises en route to clinical translation.