Natural killer (NK) cells are a viable cancer immunotherapy alternative to T cells. Clinical studies were being conducted to test adoptive therapeutics using allogeneic, cytokine-activated NK cells. The appropriate cytokine support following adoptive transfer to increase NK cell growth and persistence, on the other hand, was unknown. Correlative studies from two independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed systemic interleukin-15 (IL-15; N-803) cytokine support resulted in lower clinical activity compared to IL-2. 

Researchers postulated that the mechanism was IL-15/N-803 activating recipient CD8 T-cells, which increased donor NK cell rejection. The hypothesis was validated by higher proliferating CD8+ T-cell counts in patients treated with IL-15/N-803 versus IL-2. Furthermore, in mixed lymphocyte responses, IL-15/N-803 increased responder CD8 T-cell activation and proliferation when compared to IL-2 alone. Furthermore, IL-15/N-803 increased the capacity of responder T cells to eliminate stimulator-derived memory-like NK cells, suggesting that more IL-15 could speed up donor NK cell removal. 

As a result, using systemic IL-15 to assist allogeneic cell treatment might paradoxically reduce their therapeutic window of opportunity and clinical efficacy. The study suggested that inducing patient CD8 T-cell allo-rejection responses might severely restrict allogeneic cellular treatment with IL-15.