Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation

Nirali N. Shah, Kristin Baird, Cynthia P. Delbrook, Thomas A. Fleisher, Mark E. Kohler, Shakuntala Rampertaap, Kimberly Lemberg, Carolyn K. Hurley, David E. Kleiner, Melinda S. Merchant, Stefania Pittaluga, Marianna Sabatino, David F. Stroncek, Alan S. Wayne, Hua Zhang, Terry J. Fry, Crystal L. Mackall

Research output: Contribution to journalArticle

Abstract

Natural killer (NK) cells can enhance engraftment and mediate graft-versus-leukemia following allogeneic hematopoietic stem cell transplantation (HSCT), but the potency of graft-versus-leukemia mediated by naturally reconstituting NK cells following HSCT is limited. Preclinical studies demonstrate that activation of NK cells using interleukin-15 (IL-15) plus 4-1BBL upregulates activating receptor expression and augments killing capacity. In an effort to amplify the beneficial effects of NKcells post-HSCT,we conducted a first-in-human trial of adoptive transfer of donor-derived IL-15/4-1BBL-activated NK cells (aNK-DLI) following HLA-matched, T-cell-depleted (1-2 × 104 T cells/kg) nonmyeloablative peripheral blood stem cell transplantation in children and young adults with ultra-high-risk solid tumors. aNK-DLI were CD3+-depleted, CD56+-selected lymphocytes, cultured for 9 to 11 days with recombinant human IL-15 plus 4-1BBL+IL-15Rα+ artificial antigen-presenting cells. aNK-DLI demonstrated potent killing capacity and displayed high levels of activating receptor expression. Five of 9 transplant recipients experienced acute graft-versus-host disease (GVHD) following aNK-DLI, with grade 4 GVHD observed in 3 subjects. GVHD was more common in matched unrelated donor vs matched sibling donor recipients and was associated with higher donor CD3 chimerism. Given that the T-cell dose was below the threshold required for GVHD in this setting, we conclude that aNK-DLI contributed to the acute GVHD observed, likely by augmenting underlying T-cell alloreactivity. This trial was registered at www.clinicaltrials.gov as #NCT01287104.

Original languageEnglish (US)
Pages (from-to)784-792
Number of pages9
JournalBlood
Volume125
Issue number5
DOIs
StatePublished - Jan 29 2015

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Shah, N. N., Baird, K., Delbrook, C. P., Fleisher, T. A., Kohler, M. E., Rampertaap, S., Lemberg, K., Hurley, C. K., Kleiner, D. E., Merchant, M. S., Pittaluga, S., Sabatino, M., Stroncek, D. F., Wayne, A. S., Zhang, H., Fry, T. J., & Mackall, C. L. (2015). Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation. Blood, 125(5), 784-792. https://doi.org/10.1182/blood-2014-07-592881