Using CAR-NK cells to overcome the host resistance to antibody immunotherapy and immune checkpoint blockade therapy

The objective of this review is to promote the idea of using CAR-NK cells to overcome host resistance to therapeutic antibody and immune checkpoint blockade immunotherapies in the current clinical practice. Antibody (Ab) and immune checkpoint blockade therapy (ICBT) are promising cancer immunotherapeutic approaches. Immune cells from the host are required for both therapies to be effective. For instance, natural killer (NK) cells are required for therapeutic Ab to kill tumor cells by mediating antibody-dependent cell-mediated cytotoxicity (ADCC), whereas PD-1-positive immune cells are needed for immune checkpoint inhibitors (ICIs) to be effective in cancer treatment. However, clinical data suggest that host resistance can and actually often contributes to reduce the effects of antibody and ICBT in patients. Specifically, NK cell impairment is often observed in cancer patients and can contribute to the host resistance to therapeutic antibodies, while the lack of PD-1-positive immune infiltration contributes to the host resistance to ICBT. Here, we propose to use chimeric antigen receptor (CAR)-modified NK cells to overcome host resistances. Our published study demonstrated that the tissue factor (also known as CD142)-recognizing CAR-NK cells could mediate ADCC as effector cells via CD16, while they also could directly kill cancer cells via CAR. These findings suggest that CAR-NK cells may enhance the antibody efficacy by overcoming NK impairment in cancer patients. CAR-NK cells are also positive for expression of PD-1, which may increase PD-1-positive immune infiltration in the tumor microenvironment when combined with ICBT, so the latter can benefit not only responders, but also nonresponding patients due to the lack of immune infiltration. We anticipate that CAR-NK cells in combination with antibody and ICBT will achieve an optimal clinical outcome for more cancer patients.