title: Acute GVHD in patients receiving IL-15/4-1BBL activated NK cells following T-cell-depleted stem cell transplantation.
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 NK cells 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 × 10(4) 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.
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Nirali N
authors.initials: NN
authors.lastname: Shah
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Kristin
authors.initials: K
authors.lastname: Baird
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Cynthia P
authors.initials: CP
authors.lastname: Delbrook
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD;
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Fleisher
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Pediatrics, Johns Hopkins Hospital, Baltimore, MD;
authors.forename: Mark E
authors.initials: ME
authors.lastname: Kohler
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD;
authors.forename: Shakuntala
authors.initials: S
authors.lastname: Rampertaap
authors.affiliation: Department of Laboratory Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD;
authors.forename: Kimberly
authors.initials: K
authors.lastname: Lemberg
authors.affiliation: Department of Oncology, Georgetown University Medical Center, Washington, DC;
authors.forename: Carolyn K
authors.initials: CK
authors.lastname: Hurley
authors.affiliation: Department of Pathology, Center for Cancer Research, National Institutes of Health, Bethesda, MD;
authors.forename: David E
authors.initials: DE
authors.lastname: Kleiner
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Melinda S
authors.initials: MS
authors.lastname: Merchant
authors.affiliation: Department of Pathology, Center for Cancer Research, National Institutes of Health, Bethesda, MD;
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Department of Transfusion Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD; and.
authors.forename: Marianna
authors.initials: M
authors.lastname: Sabatino
authors.affiliation: Department of Transfusion Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD; and.
authors.forename: David F
authors.initials: DF
authors.lastname: Stroncek
authors.affiliation: Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Wayne
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Terry J
authors.initials: TJ
authors.lastname: Fry
authors.affiliation: Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD;
authors.forename: Crystal L
authors.initials: CL
authors.lastname: Mackall
mesh_terms: D053330:4-1BB Ligand / Q000494:pharmacology*; D000208:Acute Disease; D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology*; D020544:Graft vs Leukemia Effect; D006650:Histocompatibility Testing; D006801:Humans; D019409:Interleukin-15 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D008213:Lymphocyte Activation / Q000187:drug effects; D008212:Lymphocyte Depletion; D008297:Male; D036102:Peripheral Blood Stem Cell Transplantation / Q000379:methods*; D035781:Siblings; D012878:Skin Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous; D017211:Treatment Failure; D061349:Unrelated Donors
chemical_list: D053330:4-1BB Ligand; C569274:IL15 protein, human; D019409:Interleukin-15