CMV Triplex Vaccine to Enhance Adaptive NK and T-cell Reconstitution After Autologous Hematopoietic Cell Transplantation.

Cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation (HCT) augments adaptive (CD56NKG2CCD57) natural killer (NK) and CMV-specific T cells, with potential antitumor effects. Our recent work found an association between higher abundance of adaptive NK cells after auto-HCT and lower risk of relapse in patients with multiple myeloma. Triplex vaccine is a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens, which significantly enhanced CMV-specific T-cell immune responses in allo-HCT recipients.

Terminal life history: late-life fecundity and survival in experimental populations of Drosophila melanogaster.

There are two life history landmarks that can be used to define the terminal period in individual Drosophila melanogaster females: the cessation of daily oviposition, which defines the start of the retired stage, and final oviposition, which defines the start of post-ovipository survival. The terminal period is a substantial component of D. melanogaster life history.

First-in-human trial of rhIL-15 and haploidentical natural killer cell therapy for advanced acute myeloid leukemia.

In vivo expansion of haploidentical natural killer (NK) cell infusions with interleukin-2 (IL-2) can induce remission of refractory acute myeloid leukemia, but efficacy may be hampered by concurrent stimulation of host regulatory T cells. To overcome this limitation, we substituted the NK homeostatic factor IL-15 in 2 phase 1/2 trials. Forty-two patients received either intravenous (IV) (NCT01385423) or subcutaneous (SC) (NCT02395822) recombinant human IL-15 (rhIL-15) after lymphodepleting chemotherapy and haploidentical NK cells.

Monocyte Subpopulation Recovery as Predictors of Hematopoietic Cell Transplantation Outcomes.

Monocyte recovery after hematopoietic cell transplantation (HCT) has been correlated with overall survival (OS). However, monocytes are heterogeneous and consist of classic (CD14CD16), intermediate (CD14CD16), and nonclassic (CD14CD16) subpopulations, with unique functional properties. We hypothesized that monocyte subpopulation reconstitution would vary based on allogeneic stem cell source and would be associated with outcomes.

Fecundity for free? Enhanced oviposition in longevous populations of Drosophila melanogaster.

Artificial selection for increased life span in experimental populations of Drosophila melanogaster sometimes produces long-lived populations that exhibit greater fecundity than unselected controls. The absence of a trade-off between survival and reproduction in these cases might be an artefact of the rich diet of typical lab culture; if nutritional resources are not limiting then there may be no need to trade off. Here I test the rich diet hypothesis by estimating genetic correlations between survival and age-specific fecundity in three nutritional environments.

Reproductive Homeostasis and Senescence in Drosophila melanogaster.

The homeostatic properties of reproduction in aging female Drosophila melanogaster are investigated. Classic studies based on cohort analysis suggest that homeostatic capacity declines gradually as daily oviposition rates decline in aging flies. Analysis at the level of individuals gives a very different picture: reproductive homeostasis remains relatively constant for most of adult life until a critical point when oviposition either ceases entirely or continues in dysregulated fashion.

Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples.

Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft-versus-host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α-defensin-5 (HD5) and regenerating islet-derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs).

161533 TriKE stimulates NK-cell function to overcome myeloid-derived suppressor cells in MDS.

Myelodysplastic syndrome (MDS) is a clonal heterogeneous stem cell disorder driven by multiple genetic and epigenetic alterations resulting in ineffective hematopoiesis. MDS has a high frequency of immune suppressors, including myeloid-derived suppressor cells (MDSCs), that collectively result in a poor immune response. MDSCs in MDS patients express CD155 that ligates the T-cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT) and delivers an inhibitory signal to natural killer (NK) cells.

Adaptive NK Cells Resist Regulatory T-cell Suppression Driven by IL37.

Natural killer (NK) cells are capable of fighting viral infections and cancer. However, these responses are inhibited by immune suppressor cells in the tumor microenvironment. Tumor progression promotes the recruitment and generation of intratumoral regulatory T cells (Treg), associated with a poor prognosis in cancer patients.

Delayed immune reconstitution after allogeneic transplantation increases the risks of mortality and chronic GVHD.

Slow immune reconstitution is a major obstacle to the successful use of allogeneic hematopoietic cell transplantation (allo-HCT). As matched sibling donor (MSD) allo-HCT is regarded as the gold standard, we evaluated the pace of immune reconstitution in 157 adult recipients of reduced-intensity conditioning followed by MSD peripheral blood HCT (n = 68) and compared these to recipients of umbilical cord blood (UCB; n = 89). At day 28, UCB recipients had fewer natural killer (NK) cells than MSD recipients, but thereafter, NK cell numbers (and their subsets) were higher in UCB recipients.

A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 10 (n = 3), 1 × 10 (n = 3), and 3 × 10 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence.

Clinical-scale production of cGMP compliant CD3/CD19 cell-depleted NK cells in the evolution of NK cell immunotherapy at a single institution.

Background: Allogeneic natural killer (NK) cell adoptive immunotherapy is a growing therapeutic option for patients. Clinical-scale production of NK cells using immunomagnetic selection complies with current good manufacturing practices (cGMPs) and allows for closed-system, automated purification. We report our experience with CD3/CD19 cell-depleted (CD3/CD19 ) NK cell production and compare to previous methods of CD3 cell depletion and CD3 cell depletion/CD56 cell enrichment.

Early Reconstitution of NK and γδ T Cells and Its Implication for the Design of Post-Transplant Immunotherapy.

Relapse is the most frequent cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Natural killer (NK) cells and γδ T cells reconstitute early after allo-HSCT, contribute to tumor immunosurveillance via major histocompatibility complex-independent mechanisms and do not induce graft-versus-host disease. Here we performed a quantitative and qualitative analysis of the NK and γδ T cell repertoire in healthy individuals, recipients of HLA-matched sibling or unrelated donor allo-HSCT (MSD/MUD-HSCT) and umbilical cord blood-HSCT (UCB-HSCT).

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells.

We report a novel phase 2 clinical trial in patients with poor prognosis refractory non-Hodgkin lymphoma (NHL) testing the efficacy of haploidentical donor natural killer (NK) cell therapy (NK dose 0.5-3.27 × 10 NK cells/kg) with rituximab and IL-2 (clinicaltrials.

Fewer Circulating Natural Killer Cells 28 Days After Double Cord Blood Transplantation Predicts Inferior Survival and IL-15 Response.

Natural Killer (NK) cell immune reconstitution after double umbilical cord blood transplantation (dUCBT) is rapid and thought to be involved in graft vs. leukemia (GvL) reactions. To investigate the role of NK cell recovery on clinical outcomes, the absolute number of NK cells at Day 28 after dUCBT was determined and patients with low numbers of NK cells had inferior two year disease-free survival (hazard ratio 1.

Dendritic Cell Recovery Impacts Outcomes after Umbilical Cord Blood and Sibling Donor Transplantation for Hematologic Malignancies.

Dendritic cells (DCs) orchestrate immune responses after allogeneic hematopoietic cell transplantation (HCT). We studied the association of donor myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) recovery in the landmark analysis of umbilical cord blood (UCB) and matched related donor (RD) HCT. Eighty patients (42 UCB and 38 RD recipients) with a day 100 blood sample were included in the analysis.

Optimization of cGMP purification and expansion of umbilical cord blood-derived T-regulatory cells in support of first-in-human clinical trials.

Background Aims: Thymic-derived regulatory T cells (tTreg) are critical regulators of the immune system. Adoptive tTreg transfer is a curative therapy for murine models of autoimmunity, graft rejection, and graft-versus-host disease (GVHD). We previously completed a "first-in-human" clinical trial using in vitro expanded umbilical cord blood (UCB)-derived tTreg to prevent GVHD in patients undergoing UCB hematopoietic stem cell transplantation (HSCT).

Retired flies, hidden plateaus, and the evolution of senescence in Drosophila melanogaster.

Late-life plateaus in age-specific mortality have been an evolutionary and biodemographic puzzle for decades. Although classic theory on the evolution of senescence predicts late-life walls of death, observations in experimental organisms document the opposite trend: a slowing in the rate of increase of mortality at advanced ages. Here, I analyze published life-history data on individual Drosophila melanogaster females and argue for a fundamental change in our understanding of mortality in this important model system.

Umbilical cord blood-derived T regulatory cells to prevent GVHD: kinetics, toxicity profile, and clinical effect.

We studied the safety and clinical outcomes of patients treated with umbilical cord blood (UCB)-derived regulatory T cells (Tregs) that expanded in cultures stimulated with K562 cells modified to express the high-affinity Fc receptor (CD64) and CD86, the natural ligand of CD28 (KT64/86). Eleven patients were treated with Treg doses from 3-100 × 10(6) Treg/kg. The median proportion of CD4(+)FoxP3(+)CD127(-) in the infused product was 87% (range, 78%-95%), and we observed no dose-limiting infusional adverse events.

The Retired Fly: Detecting Life History Transition in Individual Drosophila melanogaster Females.

Life history observations at the level of individual model organisms are relatively scarce, but highly informative. Here I analyze published data on the survival and lifetime fecundity of 3,971 individually housed, mated Drosophila melanogaster females from nine experimental populations. Data were collected from four laboratories and include counts of over 4.

On the analysis and interpretation of late-life fecundity in Drosophila melanogaster.

Late-life plateaus have been described in both cohort and individual trajectories of fecundity in Drosophila melanogaster females. Here I examine life history data recently analyzed by Le Bourg and Moreau (2014) and show that non-linearity in the cohort trajectory of fecundity is largely explained by heterogeneity in the duration of reproductive life spans. A model specifying linear post-peak decline of fecundity in individual flies provides a better fit to the data than one that combines linear decline with late-life fecundity plateaus.

Postthaw characterization of umbilical cord blood: markers of storage lesion.

Background: The continued growth in the uses of umbilical cord blood (UCB) will require the development of meaningful postthaw quality assays. This study examines both conventional and new measures for assessing UCB quality after long-term storage.

Study Design And Methods: The first arm of the study involved thawing UCB in storage for short (approx.

Expansion and homing of adoptively transferred human natural killer cells in immunodeficient mice varies with product preparation and in vivo cytokine administration: implications for clinical therapy.

Natural killer (NK) cell efficacy correlates with in vivo proliferation, and we hypothesize that NK cell product manipulations may optimize this endpoint. Xenotransplantation was used to compare good manufacturing practice (GMP) grade freshly activated NK cells (FA-NK) and ex vivo expanded NK cells (Ex-NK). Cells were infused into NOD scid IL2 receptor gamma chain knockout (NSG) mice followed by IL-2, IL-15, or no cytokines.