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 A Cooley, Claudio G 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

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

Bibliographical note

Funding Information:
Conflict-of-interest disclosure: M.M.B.-E. and T.A.F. consult for Wugen (equity) and are inventors of technology that Washington University has licensed to Wugen (royalties). T.A.F. has received research support from Immunity Bio, Compass Therapeutics, HCW Biologics, and Wugen and advises Kiadis, Nkarta, Indapta, and Orca Biosystems. C.B. has received research funds from Gamida Cell and Fate Therapeutics and consults for Allovir (data and safety monitoring board). I.P. is on the advisory board for Incyte, Kadmon, and Syndax. J.S.M. reports consultancy, patents, royalties, and research funding from Fate Therapeutics and GT Biopharma; consultancy for Vycellix; and honoraria and membership on the advisory committees of ONK Therapeutics and Sanofi. P.S.-S. is a majority shareholder of ImmunityBio, Inc., and Altor BioScience, LLC, related to N-803. The remaining authors declare no competing financial interests.

Funding Information:
The authors acknowledge support from Bill Eades, Siteman Flow Cytometry Core; Stephen Oh, Immune Monitoring Laboratory; and Biological Therapy Core Facility of the Siteman Cancer Center supported by the National Institutes of Health National Cancer Institute Cancer Center Support Grant (P30CA91842). T.A.F. reports grants from National Institutes of Health National Cancer Institute (R01CA205239), Leukemia and Lymphoma Society, V Foundation for Cancer Research, and Siteman Cancer Center at Washington University School of Medicine and Children's Discovery Institute. M.M.B.-E. was supported by funding from National Institutes of Health National Cancer Institute (K12CA167540). University of Minnesota studies were supported by funding to J.S.M. from National Institutes of Health National Cancer Institute (P01CA111412, P01CA65493, and R35CA197292). M.M.B.-E., T.A.F., and A.F.C. were also funded by National Institutes of Health National Cancer Institute (grant P50CA171063). P. Wong was supported by a grant from the National Institutes of Health National Heart, Lung, and Blood Institute (T32HL007088). Schemas were created using .

Publisher Copyright:
© 2022 American Society of Hematology


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

PubMed: MeSH publication types

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


Dive into the research topics of 'Systemic IL-15 promotes allogeneic cell rejection in patients treated with natural killer cell adoptive therapy'. Together they form a unique fingerprint.

Cite this