Expansion, persistence and efficacy of donor memory-like NK cells for the treatment of post-transplant relapse
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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 |
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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:The bone marrow represents the tumor microenvironment for many hematologic malignancies and a potentially critical site for alloimmunity following hematopoietic transplantation. Despite the importance of immune reconstitution (IR) post-transplant, marrow IR data are limited, and insights are largely derived from studies of peripheral blood (PB). We investigated lymphocyte IR longitudinally in marrow (n=110) and PB (n=115) samples from adults undergoing allogeneic transplantation for hematologic malignancies (n=33). This transplant cohort included a diverse representation of graft sources (mobilized peripheral blood, CD34-selected grafts, and umbilical cord blood) and degrees of HLA mismatch. Natural killer (NK) cells quickly expanded within the first 30 days post-transplant in both marrow and PB, but were then outnumbered by T cells in PB after day 100. In contrast, NK cells remained dominant in the marrow at day 100 (p<0.01, paired Wilcoxon signed-rank test), and thereafter marrow T and NK cell frequencies were similar throughout year-one. Tissue-specific features post-transplant included fewer regulatory T cells, more innate lymphoid cells, and increased CD69 expression on lymphocytes in marrow compared to PB. Furthermore, day 100 PD1 expression on marrow T cells was greater in non-relapsing patients than those who subsequently relapsed. These findings reveal persistent NK dominance of the marrow early post- transplant and suggest correlations between marrow immunity and clinical transplant outcomes.
2025-12-02 | GSE296164 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296353 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296351 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce Mouse NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary Mouse NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit Mouse NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce Mouse NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296356 | GEO
Project description:Natural killer (NK) cells are critical for the immune response to cancer. However, solid tumor-infiltrating NK cells display reduced persistence and effector functions, limiting their clinical efficacy. To understand the mechanisms that induce human NK cell dysfunction in solid tumors, we compared single-cell gene expression in patient-matched tumor-infiltrating compared to tumor-adjacent NK cells to identify unfolded protein response (UPR) genes associated with worse cancer patient survival. Primary human NK cells accumulated unfolded proteins and induced a chronic UPR response to nutrient stress from the tumor microenvironment metabolome (TMM), sufficient to cause pronounced dysfunction and decreased persistence. Mechanistically, the transcription factor Fli1 epigenetically repressed UPR genes to limit human NK cell proteostasis in the presence of the TMM. CRISPR-mediated Fli1 deletion enhanced unfolded protein clearance, persistence, and tumor control in vivo. Thus, our results suggest that the TMM is sufficient to induce human NK cell dysfunction in solid tumors through the regulation of proteostasis.
2026-02-10 | GSE296355 | GEO