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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.

Hematologic cancers that recur after allogeneic hematopoietic stem-cell transplantation are often difficult to treat. A small pilot study suggests that ipilimumab may induce durable responses in a subgroup of patients with these cancers. Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only cure for many patients who have advanced hematologic cancers, principally through the induction of a graft-versus-tumor effect. 1 Unfortunately, more than one third of patients who have undergone transplantation have a relapse of disease. 2 The prognosis for these patients is poor; the majority die within 1 year after relapse despite salvage chemotherapy, donor-lymphocyte infusion, or retransplantation. 3 – 5 Immune escape (i.e., tumor evasion of the donor immune system) contributes to relapse after allogeneic HSCT, and immune checkpoint inhibitory pathways probably play an important role. 6 The engagement of cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) and programmed . . .

A low daily dose of subcutaneous interleukin-2 increases the number and function of regulatory T cells and results in substantial improvement in about half of patients with chronic graft-versus-host disease. Allogeneic hematopoietic stem-cell transplantation (HSCT) invokes donor-derived immune responses that can result in therapeutic graft-versus-tumor activity and toxic graft-versus-host disease (GVHD). Chronic GVHD, a systemic inflammatory disorder with pleomorphic autoimmune manifestations that is associated with considerable morbidity and mortality, develops in more than half of patients who have undergone HSCT. 1 – 3 Treatment with systemic glucocorticoids has limited efficacy and substantial long-term toxicity. There is no established second-line therapy. Regulatory T (Treg) cells — as defined by expression of CD4, CD25, and transcription factor forkhead box P3 (FOXP3) — account for approximately 5 to 10% of circulating CD4+ T cells, suppress . . .

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.

INTRODUCTION:Significant knowledge gaps exist regarding clinicopathological profiling as well as treatment, surveillance, and survival of duodenal neuroendocrine tumors (dNETs).METHODS:We clinicopathologically characterized and identified racial differences among patients with dNETs at a large safety net hospital. Tumor grades were updated based on the World Health Organization 2019 NET classification, and overall survival was determined.RESULTS:We identified 17 dNETs and found no differences in clinicopathologic characteristics across racial groups. Pathological diagnosis was upgraded in 35% of dNETs, and age >65 years significantly shortened overall survival.DISCUSSION:Larger-scale studies are needed to determine the significance of these findings.