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

• Published in: Blood Vol. 139; no. 11; pp. 1670 - 1683
• Main Authors: Bednarski, Jeffrey J., Zimmerman, Clare, Berrien-Elliott, Melissa M., Foltz, Jennifer A., Becker-Hapak, Michelle, Neal, Carly C., Foster, Mark, Schappe, Timothy, McClain, Ethan, Pence, Patrick P., Desai, Sweta, Kersting-Schadek, Samantha, Wong, Pamela, Russler-Germain, David A., Fisk, Bryan, Lie, Wen-Rong, Eisele, Jeremy, Hyde, Stephanie, Bhatt, Sima T., Griffith, Obi L., Griffith, Malachi, Petti, Allegra A., Cashen, Amanda F., Fehniger, Todd A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2022; American Society of Hematology
• Subjects: Child; Hematopoietic Stem Cell Transplantation - methods; Humans; Immunobiology and Immunotherapy; Killer Cells, Natural; Leukemia, Myeloid, Acute - therapy; Transplantation, Homologous; Unrelated Donors
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021013972

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. •Immune-compatible donor memory-like NK cells expand and functionally persist for months after a single dose without exogenous cytokines.•Combined with standard therapy, donor ML NK cells safely induce remissions in poor prognosis, pediatric, relapsed AML after HCT. [Display omitted]