IL‐12/15/18‐preactivated NK cells suppress GvHD in a mouse model of mismatched hematopoietic cell transplantation

Mismatched hematopoietic cell transplants for treating leukemia are complicated by graft versus host disease (GvHD). Here, we show that adoptively transferred IL‐12/15/18‐preactivated NK cells suppress GvHD in a mouse model of fully mismatched hematopoietic cell transplantation. These IL‐12/15/18‐preactivated NK cells maintained Eomesodermin (Eomes) and T‐bet expression upon transfer and, while there was no evidence of direct killing of donor T cells or host DCs by the IL‐12/15/18‐preactivated NK cells, proliferation of donor T cells was inhibited. Strikingly, the graft versus leukemia effect mediated by donor T cells was retained, resulting in improved overall survival of mice that received lymphoma cells, donor allogeneic T cells, and IL‐12/15/18‐preactivated NK cells. These results suggest that IL‐12/15/18‐preactivated NK cells may be useful in improving immunotherapy of mismatched hematopoietic cell transplantation. Compared with previously proposed protocols, our findings suggest that in vitro NK‐cell preactivation with this cytokine cocktail offers the significant advantage that cytokines do not need to be administered systemically to sustain NK‐cell activity, thus avoiding toxicity.