Donor memory-like NK cells persist and induce remissions in pediatric patients with relapsed AML after transplant

Jeffrey J. Bednarski, Clare Zimmerman, Melissa M. Berrien-Elliott, Jennifer A. Foltz, Michelle Becker-Hapak, Carly C. Neal, Mark Foster, Timothy Schappe, Ethan McClain, Patrick P. Pence, Sweta Desai, Samantha Kersting-Schadek, Pamela Wong, David A. Russler-Germain, Bryan Fisk, Wen Rong Lie, Jeremy Eisele, Stephanie Hyde, Sima T. Bhatt, Obi L. GriffithMalachi Griffith, Allegra A. Petti, Amanda F. Cashen, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Pediatric and young adult (YA) patients with acute myeloid leukemia (AML) who relapse after allogeneic hematopoietic cell transplantation (HCT) have an extremely poor prognosis. Standard salvage chemotherapy and donor lymphocyte infusions (DLIs) have little curative potential. Previous studies showed that natural killer (NK) cells can be stimulated ex vivo with interleukin-12 (IL-12), -15, and -18 to generate memory-like (ML) NK cells with enhanced antileukemia responses. We treated 9 pediatric/YA patients with post-HCT relapsed AML with donor ML NK cells in a phase 1 trial. Patients received fludarabine, cytarabine, and filgrastim followed 2 weeks later by infusion of donor lymphocytes and ML NK cells from the original HCT donor. ML NK cells were successfully generated from haploidentical and matched-related and -unrelated donors. After infusion, donor-derived ML NK cells expanded and maintained an ML multidimensional mass cytometry phenotype for >3 months. Furthermore, ML NK cells exhibited persistent functional responses as evidenced by leukemia-triggered interferon-γ production. After DLI and ML NK cell adoptive transfer, 4 of 8 evaluable patients achieved complete remission at day 28. Two patients maintained a durable remission for >3 months, with 1 patient in remission for >2 years. No significant toxicity was experienced. This study demonstrates that, in a compatible post-HCT immune environment, donor ML NK cells robustly expand and persist with potent antileukemic activity in the absence of exogenous cytokines. ML NK cells in combination with DLI present a novel immunotherapy platform for AML that has relapsed after allogeneic HCT. This trial was registered at https://clinicaltrials.gov as #NCT03068819.

Original languageEnglish
Pages (from-to)1670-1683
Number of pages14
JournalBlood
Volume139
Issue number11
DOIs
StatePublished - Mar 17 2022

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