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

Blood. 2022 Feb 24;139(8):1177-1183. doi: 10.1182/blood.2021011532.


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allogeneic Cells / immunology
  • Antineoplastic Agents / administration & dosage*
  • CD8-Positive T-Lymphocytes / immunology*
  • Female
  • Hematopoietic Stem Cell Transplantation*
  • Humans
  • Immunotherapy, Adoptive*
  • Interleukin-15 / administration & dosage*
  • Interleukin-15 / immunology
  • Killer Cells, Natural / immunology
  • Killer Cells, Natural / transplantation*
  • Leukemia, Myeloid, Acute* / immunology
  • Leukemia, Myeloid, Acute* / therapy
  • Male
  • Recombinant Fusion Proteins / administration & dosage*


  • ALT-803
  • Antineoplastic Agents
  • IL15 protein, human
  • Interleukin-15
  • Recombinant Fusion Proteins

Associated data