Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy.

NK cells are a promising alternative to T cells for cancer immunotherapy. Adoptive therapies with allogeneic, cytokine-activated NK cells are being investigated in clinical trials. However, the optimal cytokine support after adoptive transfer to promote NK cell expansion, and persistence remains unclear. Correlative studies from two independent clinical trial cohorts treated with MHC-haploidentical NK cell therapy for relapsed/refractory AML revealed that cytokine support by systemic IL-15 (N-803) resulted in reduced clinical activity, compared to IL-2. We hypothesized that the mechanism responsible was IL-15/N-803 promoting recipient CD8 T cell activation that in turn accelerated donor NK cell rejection. This idea was supported by increased proliferating CD8+ T cell numbers in patients treated with IL-15/N-803, compared to IL2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T cell activation and proliferation, compared to IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived ML NK cells, demonstrating that additional IL-15 can hasten donor NK cell elimination. Thus, systemic IL-15 used to support allogeneic cell therapy may paradoxically limit their therapeutic window of opportunity and clinical activity. This study indicates that stimulating patient CD8 T cell allo-rejection responses may critically limit allogeneic cellular therapy supported with IL-15.