Dataset Information

Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control.

ABSTRACT: Cellular immunotherapy using allogeneic natural killer (NK) cells may overcome chemotherapy-refractory acute myeloid leukemia. Our goal was to document NK cell homing/persistence in the bone marrow following adoptive immunotherapy. Our cohort included 109 patients who received NK cell therapy for refractory acute myeloid leukemia following lymphodepleting conditioning +/- denileukin diftitox, +/- low-dose total body irradiation. We evaluated the NK cell density in bone marrow core biopsies performed an average of 14 days after NK cell transfer using a CD56 immunohistochemical stain. The NK cell density in core biopsies showed only moderate correlation with NK cell percentage in bone marrow aspirates evaluated by flow cytometry (rs=0.48) suggesting that distribution of CD56 cells in the bone marrow niche offers unique insight into NK cell homing. Better leukemia control was associated with increased NK cell density, such that patients with <5% blasts had a higher NK cell density (P=0.01). As well, NK cell density above the median of reference group was significantly associated with morphologic remission of leukemia (P=0.01). Moreover, the NK cell density varied significantly between conditioning protocols. Our findings suggest that the use of low-dose irradiation or CD25-targeting immunocytokine (denileukin diftitox, IL2DT) as part of conditioning results in increased NK cell homing/persistence in the bone marrow. These novel results will help guide future immunotherapy with NK cells.

SUBMITTER: Grzywacz B

PROVIDER: S-EPMC6365204 | biostudies-literature | 2019 Feb/Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control.

Grzywacz Bartosz B Moench Laura L McKenna David D Tessier Katelyn M KM Bachanova Veronika V Cooley Sarah S Miller Jeffrey S JS Courville Elizabeth L EL

Journal of immunotherapy (Hagerstown, Md. : 1997) 20190201 2

Cellular immunotherapy using allogeneic natural killer (NK) cells may overcome chemotherapy-refractory acute myeloid leukemia. Our goal was to document NK cell homing/persistence in the bone marrow following adoptive immunotherapy. Our cohort included 109 patients who received NK cell therapy for refractory acute myeloid leukemia following lymphodepleting conditioning +/- denileukin diftitox, +/- low-dose total body irradiation. We evaluated the NK cell density in bone marrow core biopsies perfo ...[more]

PMID: 30489431

Similar Datasets

Project description:Adoptive transfer of natural killer (NK) cells can induce remission in patients with relapsed/refractory leukemia and myeloma. However, to date, clinical efficacy of NK cell immunotherapy has been limited to a sub-fraction of patients. Here we show that steps incorporated in the ex vivo manipulation/production of NK cell products used for adoptive infusion, such as over-night IL-2 activation or cryopreservation followed by ex vivo expansion, drastically decreases NK cell surface expression of the bone marrow (BM) homing chemokine receptor CXCR4. Reduced CXCR4 expression was associated with dampened in vitro NK cell migration toward its cognate ligand stromal-derived factor-1α (SDF-1α). NK cells isolated from patients with WHIM syndrome carry gain-of-function (GOF) mutations in CXCR4 (CXCR4R334X). Compared to healthy donors, we observed that NK cells expanded from WHIM patients have similar surface levels of CXCR4 but have a much stronger propensity to home to BM compartments when adoptively infused into NOD-scid IL2Rgammanull (NSG) mice. Therefore, in order to augment the capacity of adoptively infused NK cells to home to the BM, we genetically engineered ex vivo expanded NK cells to express the naturally occurring GOF CXCR4R334X receptor variant. Transfection of CXCR4R334X-coding mRNA into ex vivo expanded NK cells using a clinically applicable method consistently led to an increase in cell surface CXCR4 without altering NK cell phenotype, cytotoxic function, or compromising NK cell viability. Compared to non-transfected and wild type CXCR4-coding mRNA transfected counterparts, CXCR4R334X-engineered NK cells had significantly greater chemotaxis toward SDF-1α in vitro. Importantly, expression of CXCR4R334X on expanded NK cells resulted in significantly greater BM homing following adoptive transfer into NSG mice compared to non-transfected NK cell controls. Collectively, these data suggest up-regulation of cell surface CXCR4R334X on ex vivo expanded NK cells via mRNA transfection represents a novel approach to improve homing and target NK cell-based immunotherapies to BM where hematological malignancies reside.

Dataset Information

Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control.

Publications

Natural Killer Cell Homing and Persistence in the Bone Marrow After Adoptive Immunotherapy Correlates With Better Leukemia Control.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets