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

Melissa M. Berrien-Elliott, Michelle Becker-Hapak, Amanda F. Cashen, Miriam Jacobs, Pamela Wong, Mark Foster, Ethan McClain, Sweta Desai, Patrick Pence, Sarah Cooley, Claudio Brunstein, Feng Gao, Camille N. Abboud, Geoffrey L. Uy, Peter Westervelt, Meagan A. Jacoby, Iskra Pusic, Keith E. Stockerl-Goldstein, Mark A. Schroeder, John F. DiPersioPatrick Soon-Shiong, Jeffrey S. Miller, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


Natural killer (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 2 independent clinical trial cohorts treated with major histocompatibility complex-haploidentical NK cell therapy for relapsed/refractory acute myeloid leukemia revealed that cytokine support by systemic interleukin-15 (IL-15; N-803) resulted in reduced clinical activity, compared with 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 with IL-2. Moreover, mixed lymphocyte reactions showed that IL-15/N-803 enhanced responder CD8 T-cell activation and proliferation, compared with IL-2 alone. Additionally, IL-15/N-803 accelerated the ability of responding T cells to kill stimulator-derived memory-like 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. This trial was registered at as #NCT03050216 and #NCT01898793.

Original languageEnglish
Pages (from-to)1177-1183
Number of pages7
Issue number8
StatePublished - Feb 24 2022


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