The Engineering of Natural Killer Cells as an Emerging Adoptive Cancer Immunotherapy

Abstract

2006). The tumors disappeared, presumably because they were attacked by the improved immune system. Seeing that the results were positive, his approach caught on. In recent years, the most prominent immunomodulatory strategy has been using chimeric antigen receptor T-cell (CAR-T) immunotherapy, which has had striking complete remission (CR) rates as high as 90% in acute lymphoblastic leukemia (ALL).Unfortunately, CAR-T cells have some significant limitations. One of the major hardships with the generation of an autologous CAR-T cell product is that it is derived from each patient individually, making it too difficult to scale for widespread clinical use. In fact, it takes a minimum of two to three weeks to manufacture CAR-T cells (Hay and Turtle, 2017). Therefore, for a patient in critical condition with a rapidly advancing disease, treatment with CAR-T cells would be impractical. Additionally, it is difficult to collect the required quantity of lymphocytes from patients to generate CAR-T cells. And, in the case of allogenic T cells, which are transported from a donor, they can cause graft-versus-host disease (GVHD) (Liu et al., 2017).The newly discovered CAR NK cells are perhaps more promising than the CAR-T cells. NK cells are cytotoxic, or cell-killing, and kill their targets in a non-specific manner. This means NK cells don't have to recognize a specific antigen on viral-infected cells or cancer cells (Farag and Caligiuri, 2006: Locatelli et al., 2014). Consequently, this enhances their immunosurveillance. The NK cells decide whether to kill cells based on signals from activating and inhibitory receptors on the NK cell surface. While activating receptors 'switch on' the NK cell when recognizing cell-surface molecules expressed on cancer cells, inhibitory receptors 'switch off' the NK cell and prevent it from killing cells pos-

Current Perspectives on “Off-The-Shelf” Allogeneic NK and CAR-NK Cell Therapies

“…Gene transfer did not change the function or phenotype of NK cells, nor did it change the proliferative or cytotoxic ability post engineering. Another recent study used retroviral vector systems that ectopically expressed iC9/CAR.19/IL15 to generate CAR-CD19-NK cells from cord blood that persisted for a long time in the tumor microenvironment ( 110 , 111 ). In both studies, the retroviral vector ectopically produced IL15 that is crucial for NK cell survival and conditionally expressed a caspase 9 (iC9)- an inducible suicide gene that could be activated to shut off the system by eliminating transduced cells when needed.…”