Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA813854 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR18324462_1.fastq.gz | Fastqsanger.gz | |||
| SRR18324462_2.fastq.gz | Fastqsanger.gz | |||
| SRR18324463_1.fastq.gz | Fastqsanger.gz | |||
| SRR18324463_2.fastq.gz | Fastqsanger.gz | |||
| SRR18324464_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 34 |
Similar Datasets
Project description:Relapse of AML occurs in up to 50% of patients after allogeneic hematopoietic stem cell transplant (HCT) and heralds an extremely poor prognosis. Cytokine induced memory-like (CIML) human NK cells have enhanced ability to recognize and kill leukemia targets. We initiated a phase I trial of CIML NK cells to treat patients with relapsed myeloid malignancies after haplo-HCT (NCT04024761). Transcriptional profiling analysis by scRNAseq were used to characterize the immunophenotypes of infused NK cells post cell adoptive transfer and as well as their interactions with tumor cells.
2022-03-11 | GSE198141 | GEO
Project description: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.
| S-EPMC9151697 | biostudies-literature
Project description:In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 105-1 × 108 cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).
| S-EPMC8727305 | biostudies-literature
Project description:NK cells recruitment into the skin in response to an NK cell activating ligand (m157) and absence of MHC class I expression (B2m knockout) alters the transcriptional profile of the cells compared with circulating NK cells. In this experiment, we compared the gene expression profile of conventional NK cells in circulation with those entering the skin post-transplant as well as with tissue-resident NK cells.
2022-04-06 | GSE148600 | GEO
Project description:Single-cell transcriptomics was performed to investigate the bone marrow NK cell compartment of myeloma patients at diagnosis (n=19), during treatment (n=21) and at relapse (n=6). The bone marrow of myeloma patients is characterized by a reduction in conventional cytotoxic NK cells that persists throughout treatment. We show in 20% of newly diagnosed myeloma patients that an altered balance between cytotoxic and cytokine-producing NK cells translates into a reduced cytotoxic ability in response to therapeutic antibodies. The relative loss of cytotoxic NK cells persists at relapse and is accompanied by an expansion of IFN-responsive NK cells. These findings reveal previously unappreciated alterations in bone marrow NK cell composition and highlight the importance of understanding the bone marrow immune system in patients receiving immunotherapies.
2023-07-18 | E-MTAB-13157 | biostudies-arrayexpress
Project description:Patients with acute leukemia who are unable to achieve complete remission prior to allogeneic hematopoietic stem cell transplantation (SCT) have dismal outcomes with relapse rates well in excess of 60%. Haplo-identical SCT (haplo-SCT) may allow enhanced graft-versus-leukemia (GVL) effects by virtue of HLA class I/II donor-host disparities but typically requires intensive immune-suppression with post-transplant cyclophosphamide (PT-Cy) to prevent lethal graft-versus-host disease (GVHD). Here we demonstrate in preclinical models that glucocorticoid administration from day -1 to +5 inhibits alloantigen presentation by professional recipient antigen presenting cells in the gastrointestinal tract and prevents donor T-cell priming and subsequent expansion therein. In contrast, direct glucocorticoid signaling of donor T-cells promotes chemokine and integrin signatures permissive of preferential circulation and migration into the bone marrow, promoting donor T-cell residency.
2021-10-31 | GSE184963 | GEO
Project description:Lymphocyte subsets (CD8, CD4 Tconv, NK cells) were sorted from patients' peripheral blood obtained on day 28 after haploidentical-donor allogeneic bone marrow transplantation followed by posttransplant cyclophosphamide (PTCy), tacrolimus, and MMF as GVHD prophylaxis (NCT00796562). Cohort of patients developed GVHD, or remained GVHD-free. Cohort of patients developed disease relapse, or remained relapse-free. RNA-sequencing was performed to analyze the transcriptional landscape of alloresponse in post-PTCy breakthrough GVHD and relapse.
2021-09-28 | GSE182612 | GEO
Project description:SARS-CoV-2 RNA generally becomes undetectable in upper airways after a few days or weeks post-infection. It is unclear however if the virus persists in other parts of the body and which mechanism(s) regulate SARS-CoV-2 persistence. We addressed this question in the macaque model. Replication-competent virus was detected in bronchioalveolar lavages (BAL) macrophages beyond 6 months post-infection. SARS-CoV-2 propagated in BAL macrophages from cell-to-cell. IFN-γ inhibited this replication. IFN-γ production within BAL lymphocytes was strongest in NKG2r+CD8+ T and NKG2Alo NK cells and was further increased in NKG2Alo NK cells after Spike protein stimulation. However, IFN-γ production was impaired in NK cells from animals with persisting virus. IFN-γ also enhanced MHC-E expression on BAL macrophages, possibly inhibiting natural killer cell mediated killing. Animals with less persisting virus mounted adaptive NK cells escaping this MHC-E dependent inhibition. Our findings reveal an interplay between NK cells and macrophages mediated by IFN-γ, regulating SARS-CoV-2 persistence in macrophages. Gene expression in bronchoalveolar lavage fluid (BALF) NK cells in SARS-CoV-2 convalescent monkeys.
2023-09-25 | GSE243732 | GEO
Project description:SARS-CoV-2 RNA generally becomes undetectable in upper airways after a few days or weeks post-infection. It is unclear however if the virus persists in other parts of the body and which mechanism(s) regulate SARS-CoV-2 persistence. We addressed this question in the macaque model. Replication-competent virus was detected in bronchioalveolar lavages (BAL) macrophages beyond 6 months post-infection. SARS-CoV-2 propagated in BAL macrophages from cell-to-cell. IFN-γ inhibited this replication. IFN-γ production within BAL lymphocytes was strongest in NKG2r+CD8+ T and NKG2Alo NK cells and was further increased in NKG2Alo NK cells after Spike protein stimulation. However, IFN-γ production was impaired in NK cells from animals with persisting virus. IFN-γ also enhanced MHC-E expression on BAL macrophages, possibly inhibiting natural killer cell mediated killing. Animals with less persisting virus mounted adaptive NK cells escaping this MHC-E dependent inhibition. Our findings reveal an interplay between NK cells and macrophages mediated by IFN-γ, regulating SARS-CoV-2 persistence in macrophages. Gene expression in bronchoalveolar lavage fluid (BALF) NK cells in SARS-CoV-2 convalescent monkeys.
2023-09-25 | GSE243733 | GEO
Project description:T cell mediated rejection (TCMR) affects ∼50% of pediatric liver transplant recipients within 5 years, and late TCMR is associated with graft failure due to ineffective treatment. Although CD8+ T cells promote late TCMR, their clonal expansion, intragraft persistence, localization, and gene expression remain largely undefined. Herein, single-cell RNA sequencing and immune repertoire profiling of 30 cryopreserved liver biopsies from rejecting and non-rejecting pediatric patients identified expanded intragraft CD8+ T cell clonotypes (CD8EXP) and their gene expression profiles. Expanded CD8+ clonotypes (CD8EXP) bore markers of effector and CD56hiCD161- 'NK-like' T cells, retaining their clonotype identity and phenotype in serial biopsies despite histologic TCMR resolution. CD8EXP clonotypes localized to portal infiltrates during active TCMR and persisted in the lobule after histologic TCMR resolution. MultiNicheNet analysis revealed differential crosstalk between Kupffer cells (KC) and CD8EXP, with activation of TGFß and downregulation of CD47 immune checkpoint signaling. Therefore, persistenting intragraft CD8EXP clones remain active despite TCMR treatment and may contribute to long-term allograft fibrosis and failure of operational tolerance.
2025-08-20 | GSE256141 | GEO