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BackgroundResponses to conventional donor lymphocyte infusion for postallogeneic hematopoietic cell transplantation (HCT) relapse are typically poor. Natural killer (NK) cell-based therapy is a promising modality to treat post-HCT relapse.MethodsWe initiated this ongoing phase I trial of adoptively transferred cytokine-induced memory-like (CIML) NK cells in patients with myeloid malignancies who relapsed after haploidentical HCT. All patients received a donor-derived NK cell dose of 5 to 10 million cells/kg after lymphodepleting chemotherapy, followed by systemic IL-2 for 7 doses. High-resolution profiling with mass cytometry and single-cell RNA sequencing characterized the expanding and persistent NK cell subpopulations in a longitudinal manner after infusion.ResultsIn the first 6 enrolled patients on the trial, infusion of CIML NK cells led to a rapid 10- to 50-fold in vivo expansion that was sustained over months. The infusion was well tolerated, with fever and pancytopenia as the most common adverse events. Expansion of NK cells was distinct from IL-2 effects on endogenous post-HCT NK cells, and not dependent on CMV viremia. Immunophenotypic and transcriptional profiling revealed a dynamic evolution of the activated CIML NK cell phenotype, superimposed on the natural variation in donor NK cell repertoires.ConclusionGiven their rapid expansion and long-term persistence in an immune-compatible environment, CIML NK cells serve as a promising platform for the treatment of posttransplant relapse of myeloid disease. Further characterization of their unique in vivo biology and interaction with both T cells and tumor targets will lead to improvements in cell-based immunotherapies.Trial RegistrationClinicalTrials.gov NCT04024761.FundingDunkin' Donuts, NIH/National Cancer Institute, and the Leukemia and Lymphoma Society.

In this study of unrelated-donor transplantation for hematologic cancers, survival was similar with bone marrow and peripheral-blood stem-cell grafts. However, graft failure was more common with the former, and chronic graft-versus-host disease with the latter. In the early days of allogeneic hematopoietic stem-cell transplantation, the only graft source available was bone marrow harvested from the pelvis of a donor under anesthesia. When studies showed that an increased dose of bone marrow cells correlated with more robust hematopoietic engraftment and lower mortality from infectious complications, transplantation centers began to use filgrastim-stimulated peripheral blood, which has a much higher content of blood progenitor cells than bone marrow, although there was concern that the higher T-cell content might increase the risk of graft-versus-host disease (GVHD). 1 – 5 Several large, randomized trials of transplantation between HLA-identical siblings showed that peripheral-blood . . .

A study in patients with chronic GVHD evaluated three doses of axatilimab, a colony-stimulating factor 1 receptor antibody. The lowest dose appeared to maximize response with the fewest adverse effects.

Graft-versus-host disease (GVHD) is a major cause of morbidity and mortality in hematopoietic stem cell transplantation (HSCT). Donor T cells are key mediators in pathogenesis, but a contribution from host T cells has not been explored, as conditioning regimens are believed to deplete host T cells. To evaluate a potential role for host T cells in GVHD, the origin of skin and blood T cells was assessed prospectively in patients after HSCT in the absence of GVHD. While blood contained primarily donor-derived T cells, most T cells in the skin were host derived. We next examined patient skin, colon, and blood during acute GVHD. Host T cells were present in all skin and colon acute GVHD specimens studied, yet were largely absent in blood. We observed acute skin GVHD in the presence of 100% host T cells. Analysis demonstrated that a subset of host T cells in peripheral tissues were proliferating (Ki67+) and producing the proinflammatory cytokines IFN-γ and IL-17 in situ. Comparatively, the majority of antigen-presenting cells (APCs) in tissue in acute GVHD were donor derived, and donor-derived APCs were observed directly adjacent to host T cells. A humanized mouse model demonstrated that host skin-resident T cells could be activated by donor monocytes to generate a GVHD-like dermatitis. Thus, host tissue-resident T cells may play a previously unappreciated pathogenic role in acute GVHD.

Crop yields in food and fibre production systems throughout the world are significantly limited by soil water deficits. Identifying water conservation mechanisms within existing genotypes is pivotal in developing varieties with improved performance in water-limited conditions. The objective of this study was to screen Australian germplasm for variability in the transpiration response to progressive soil drying using a glasshouse dry-down experiment. It tests the hypothesis that water conservation traits may provide tolerance to water stress, particularly when combined with other drought stress traits. Three glasshouse experiments were conducted to identify whether there are differences in the fraction of transpirable soil water (FTSW) threshold values for transpiration decline among six cotton genotypes. We also assessed whether genotype dependent responses to progressive soil drying are evident from leaf-level physiology, by measurement of gas exchange parameters. Significant variation in the FTSW threshold for transpiration decline between six genotypes was found, ranging from 0.13 to 0.29. Genotypic variation in the response to soil drying was also observed from leaf level physiology, with reductions in stomatal conductance and photosynthetic rate coinciding with when the FTSW threshold was reached. Genotypes that limit transpiration at high FTSW can conserve water earlier in the season to maintain productivity during extended dry periods. Therefore, these genotypes may provide physiological traits that improve productivity in water-limited environments. This research is important as rainfall and water resources for irrigated agriculture are predicted to decline. The development of drought tolerant germplasm for the Australian cotton industry will be beneficial in the projected increasingly frequent limited water environments resulting from a changing climate.

Allogeneic hematopoietic stem cell transplantation (HSCT) recipients often experience deficits in positive psychological well-being (PPWB) due to intensive treatment and follow-up care. Positive psychology interventions (PPIs) that promote PPWB via deliberate and systematic exercises (e.g., writing a gratitude letter) have consistently improved PPWB in medical populations, yet have never been studied in early HSCT recovery. In this single-arm, proof-of-concept study, we assessed the feasibility and acceptability of a novel eight-session, telephone-delivered PPI in early HSCT recovery. A priori, we defined feasibility as >50% of eligible patients enrolling in the study and >50% of participants completing 5/8 sessions, and acceptability as mean ease and utility scores of weekly participant ratings of PP exercises as 7/10. Of 45 eligible patients, 25 (55.6%) enrolled, 20 (80%) completed baseline assessments, 15 (75%) started the intervention, and 12 (60%) completed the intervention and follow-up assessments. The intervention was feasible (55.6% of eligible participants enrolled; 60% of baseline assessment completers finished 5/8 sessions) and led to very small-to-medium effect-size improvements in patient-reported outcomes. A novel, eight-week, telephone-delivered PPI was feasible and acceptable in allogeneic HSCT recipients. Larger, randomized studies are needed to examine the efficacy of PPIs for improving outcomes in this population.

Recurrent mutations in TP53, RAS pathway and JAK2 genes were shown to be highly prognostic of allogeneic hematopoietic cell transplant (alloHCT) outcomes in myelodysplastic syndromes (MDS). However, a significant proportion of MDS patients has no such mutations. Whole-genome sequencing (WGS) empowers the discovery of novel prognostic genetic alterations. We conducted WGS on pre-alloHCT whole-blood samples from 494 MDS patients. To nominate genomic candidates and subgroups that are associated with overall survival, we ran genome-wide association tests via gene-based, sliding window and cluster-based multivariate proportional hazard models. We used a random survival forest (RSF) model with build-in cross-validation to develop a prognostic model from identified genomic candidates and subgroups, patient-, disease- and HCT-related clinical factors. Twelve novel regions and three molecular signatures were identified with significant associations to overall survival. Mutations in two novel genes, CHD1 and DDX11 , demonstrated a negative impact on survival in AML/MDS and lymphoid cancer data from the Cancer Genome Atlas (TCGA). From unsupervised clustering of recurrent genomic alterations, genomic subgroup with TP53 /del5q is characterized with the significant association to inferior overall survival and replicated by an independent dataset. From supervised clustering of all genomic variants, more molecular signatures related to myeloid malignancies are characterized from supervised clustering, including Fc-receptor FCGRs, catenin complex CDHs and B-cell receptor regulators MTUS2 / RFTN1 . The RSF model with genomic candidates and subgroups, and clinical variables achieved superior performance compared to models that included only clinical variables.

The authors have identified an acute diarrheal syndrome that develops about 4 months after cord-blood hematopoietic stem-cell transplantation with the use of umbilical-cord blood. The disease is characterized by fever, watery diarrhea, and responsiveness to antibiotics. Hematopoietic stem-cell transplantation (HSCT) with the use of umbilical-cord blood is effective in patients for whom a sibling or matched, unrelated donor is not available. 1 – 4 Acute graft-versus-host disease (GVHD), a major cause of illness in patients undergoing HSCT, is less severe with cord-blood transplants than with adult donor transplants. 1 – 5 However, cord-blood HSCT is associated with an increased risk of infection related to delayed immune reconstitution because of the infusion of naive immune cells with the graft. 6 – 9 Acute GVHD and gastrointestinal infection are important causes of diarrhea after HSCT. 10 , 11 Distinguishing between them is important because their treatment . . .