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FT500 as Monotherapy and in Combination With Immune Checkpoint Inhibitors in Subjects With Advanced Solid Tumors

ABSTRACT: FT500 is an off-the-shelf, iPSC-derived NK cell product that can bridge innate and adaptive immunity, and has the potential to overcome multiple mechanisms of immune checkpoint inhibitor (ICI) resistance. The preclinical data provide compelling evidence supporting the clinical investigation of FT500 as monotherapy and in combination with ICI in participants with advanced solid tumors.

DISEASE(S): Microsatellite Instability,Carcinoma,Small Cell Lung Cancer,Egfr Positive Solid Tumor,Advanced Solid Tumors,Colorectal Cancer,Urothelial Carcinoma,Head And Neck Neoplasms,Carcinoma, Merkel Cell,Neoplasms,Pancreas Cancer,Nsclc,Gastric Cancer,Advanced Solid Tumor,Squamous Cell Carcinoma,Colorectal Neoplasms,Her2-positive Breast Cancer,Renal Cell Carcinoma,Stomach Neoplasms,Pancreatic Neoplasms,Hepatocellular Carcinoma,Cervical Cancer,Melanoma,Small Cell Lung Carcinoma,Merkel Cell Carcinoma,Breast Cancer,Lymphoma,Carcinoma, Squamous Cell,Head And Neck Cancer

PROVIDER: 2297199 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Checkpoint Inhibitors Modulate Plasticity of Innate Lymphoid Cells in Peripheral Blood of Patients with Hepatocellular Carcinoma

Project description:Introduction: The role of innate lymphoid cells (ILC) in cancer and specifically in the context of hepatocellular carcinoma (HCC) is not well understood. Immune checkpoint inhibitors (ICI) have been approved for treatment of patients with HCC. The effect of ICI on ILCs has not been explored. Methods: We studied ILCs in PBMCs of 51 patients with HCC at baseline and after treatment with ICI. Flow cytometry was used to study ILC composition. Single-cell RNA-sequencing using a targeted panel of 405 immune-related genes was used to characterize the transcriptomic profiles as well as cellular trajectory of ILCs before and after ICI therapy. Intracellular cytokine staining was used to validate ILC function. Data from large patient cohorts were used to predict association with survival. Results: Characterization of the ILC subgroups in PBMCs of HCC patients revealed a significant increase in ILC1 and a decrease in ILC3 frequencies. Single cell RNA-sequencing identified a subgroup of NK-like ILCs which expressed cytotoxicity markers as well as NKp80/KLRF1. This KLRF1high-NK-like population showed low abundance in patients with HCC and was enhanced after combined anti-CTLA-4 and anti-PD-1 immunotherapy. Trajectory analysis placed this population in between ILC1 and ILC3s. The transcriptomic signature of KLRF1high NK-like ILCs was associated with better progression-free survival in HCC cohorts. Conclusions: We present a previously unknown effect of HCC tumors and ICIs on the composition and plasticity of ILCs in PBMCs. We identified a cytotoxic KLRF1high-NK-like subgroup which was associated with better survival, absent in untreated HCC patients, and enhanced upon ICI immunotherapy. Thus, ILCs from PBMC can be used to study changes in the innate immune system under immunotherapy.

2022-06-23 | GSE195648 | GEO

Regulation of iNKT cell development and function by METTL3

Project description:Invariant natural killer T (iNKT) cells are a specific innate-like counterpart of T lymphocytes, which response to lipid-based antigens and provide a functional bridge between the innate and adaptive immunity. The physiological role of m6A modification involved in NK cells differentiation remains unclear. We found that N6-Methyladenosine (m6A) methyltransferase METTL3 is intrinsically required for iNKT cell development and function in an m6A-dependent manner. To investigate the molecular mechanisms, RNA-seq was performed using iNKT cells in thymocytes isolated from WT and KO mice to investigate the regulatory network.

2023-12-31 | GSE210324 | GEO

m6A modification in DP and iNKT cells

Project description:Invariant natural killer T (iNKT) cells are a specific innate-like counterpart of T lymphocytes, which response to lipid-based antigens and provide a functional bridge between the innate and adaptive immunity. The physiological role of m6A modification involved in NK cells differentiation remains unclear. We found that N6-Methyladenosine (m6A) methyltransferase METTL3 is intrinsically required for iNKT cell development and function in an m6A-dependent manner. To investigate the molecular mechanisms, m6A-LACE-seq was performed using iNKT cells and Merip-seq was performed using DP cells in thymocytes isolated from WT and KO mice to investigate the regulatory network.

2023-12-31 | GSE210325 | GEO

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection [scRNAseq_Ly49H+_NK_retrogenic_spleen]

Project description:Upon viral infection, NK cells expressing certain germline-encoded receptors are selected, expanded and maintained in an adaptive-like manner. Currently, these are thought to differentiate along a common pathway. However, by fate mapping of single NK cells upon murine cytomegalovirus (MCMV) infection, we identified two distinct NK cell lineages that contributed to adaptive-like responses. One was equivalent to conventional NK (cNK) cells while the other was transcriptionally similar to type 1 innate lymphoid cells (ILC1s). ILC1-like NK cells showed splenic-residency and strong cytokine production but also recognized and killed MCMV-infected cells, guided by activating receptor Ly49H. Moreover, they induced clustering of conventional type 1 dendritic cells and facilitated antigen-specific T cell priming early during MCMV infection, which depended on Ly49H and the NK cell-intrinsic expression of transcription factor Batf3. Thereby, ILC1-like NK cells bridge innate and adaptive viral recognition and unite critical features of cNK cells and ILC1s.

2021-08-25 | GSE180976 | GEO

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection [scRNAseq_spleen_Ly49H+_steady-state]

2021-08-25 | GSE180975 | GEO

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection [bulk_RNAseq_d8pi]

2021-08-25 | GSE180974 | GEO

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection [bulk_RNAseq_steady_state]

2021-08-25 | GSE180973 | GEO

Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection [scRNAseq_spleen_LN_total_NK]

2021-08-25 | GSE180977 | GEO

Differential gene expression in human myeloid dendritic cells interacting with different knockout strains of Aspergillus fumigatus in vitro

Project description:Dendritic cells (DC) are the most important antigen presenting cells and play a pivotal role in host immunity to infectious agents by acting as a bridge between the innate and adaptive immune systems. Myeloid DCs (mDC) were isolated from peripheral blood and co-cultured with conidia (con) and germlings (ks) of Aspergillus fumigatus knockout (mitA, mnt1, rodA) and wildtype (wt) strains for 6 hours at an MOI of 1. RNA was extracted and hybridised to microarrays. Microarrays contain probes for approximately 110 selected human immune-relevant genes, including cytokine and chemokine genes, their receptors and downstream innate immunity genes. We used microarrays to detail the gene expression of human myeloid dendritic cells after 6h of co-cultivation with Aspergillus fumigatus wildtype and knockout mutants

2012-04-16 | E-GEOD-34884 | biostudies-arrayexpress

Determination of cell specific regulatory enhancers in hematopoetic models

Project description:The BLUEPRINT project is a large-scale project investigating epigenetic mechanisms involved in blood formation, in health and disease. The human variation workpackage (WP10) of the project seeks to characterize the effect of common sequence variation on the epigenome status of a cell. To do this, the project will use highly purified blood cells to minimise experimental noise and therefore enhance the power to discover modest effects. Two peripheral blood cell types, the CD14+CD16- monocyte (an important central orchestrator of adaptive immunity and a bridge between innate and adaptive immunity) and the CD65+CD9- neutrophilic granulocyte (the frontline cell for innate immunity) have been selected for this purpose. The two types of cells will be obtained at high purity from adult blood (AB) of 200 healthy males and females, respectively. Cells will be purified by using already validated and fully operational protocols that are based on density gradient centrifugation of the buffy coat obtained from whole blood, followed by magnetic bead-based purification using monoclonal antibodies against Cluster of Differentiation (CD) lineage-specific cell surface markers. This data set contains functional genomics data for gene expression and chromatin state.

2015-11-17 | E-ERAD-214 | biostudies-arrayexpress

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