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Co-transplantation of CAR-gene Engineered Precursor T Cells Leads To Suppressed T Cell Development and Increased NK Cell-based CAR-mediated Anti-leukemic Activity

ABSTRACT: Co-transplantation of CAR-gene Engineered Precursor T Cells Leads To Suppressed T Cell Development and Increased NK Cell-based CAR-mediated Anti-leukemic Activity

PROVIDER: PRJNA412882 | ENA |

REPOSITORIES: ENA

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Co-transplantation of CAR-gene Engineered Precursor T Cells Leads To Suppressed T Cell Development and Increased NK Cell-based CAR-mediated Anti-leukemic Activity

Project description:CAR gene expression on precursor T cells (preTs) that have been generated in vitro from engineered hematopoietic stem cells may reduce the risk of leukemia relapse upon co-transplantation in an MHC-independent manner. Setting the expression of an anti-murine CD19 CAR under the control of an inducible promoter allowed time-dependent assessment of its impact on in vivo development. Adoptive transfer of engineered preTs along with T cell-depleted bone marrow resulted in potent anti-leukemia effects even in fully MHC-class I and II mismatched recipients. Anti-leukemia effects entirely relied on the in vivo development of CAR-expressing natural killer cells since NK cell depletion after transplantation resulted in a complete abrogation of anti-leukemic efficacy. Gene expression profiling revealed that enforced CAR expression on preTs led to an activated shift of transcriptional key factors to those being associated with NK cell development such as Nfil3, Id2, and Eomes. In contrast, CAR expression on preTs blocked thymic seeding completely and prevented further T cell development. The CAR-expressing NK cell progeny of transferred preTs persisted for up to 60 days post transplantation allowing for complete B-cell recovery thereafter. Taken together, we provide new functional insights for the use of CAR-engineered preTs allowing for potent anti-leukemia efficiency within a limited time window for on target/off tumor effects.

2017-10-03 | GSE104512 | GEO

Multi-Omic Single-Cell Dissection of Leukemic T-Cell Lymphoma Following CAR T-Cell Therapy [Spatial Transcriptomics]

Project description:A 63-year-old male who received ciltacabtagene autoleucel (cilta-cel) CAR-T cells and the GPRC5DxCD3 bispecific talquetamab for early relapse of his multiple myeloma (MM) developed a leukemic peripheral T-cell lymphoma (PTCL) with cutaneous and intestinal involvement. Longitudinal single-cell RNA and T-cell receptor sequencing of peripheral blood and bone marrow revealed two hyperexpanded CAR-carrying, exhausted effector-memory T-cell clones with marked immunophenotypic as well as transcriptional alterations and different susceptibilities towards treatment with dexamethasone. Spatial transcriptomes of skin lesions confirmed the aberrant CAR-expressing T cells. Whole genome sequencing revealed three distinct integration sites, within the introns of ZGPAT, KPNA4, and polycomb-associated non-coding RNAs. Pre/post-CAR-T whole-genome analyses implicated clonal outgrowth of a TET2-mutated precursor propelled by additional sub-clone specific LOH and other secondary mechanisms

2025-01-05 | GSE283145 | GEO

Multi-Omic Single-Cell Dissection of Leukemic T-Cell Lymphoma Following CAR T-Cell Therapy [scRNA-seq]

2025-01-05 | GSE283144 | GEO

Monocyte-derived IL-1 and IL-6 are differentially required for cytokine release syndrome and neurotoxicity by CAR-T cells.

Project description:Single-cell transcriptome profiling using a 3' droplet-based platform (Chromium,10x Genomics) of human CD45+ leukocytes isolated from leukemic HuSGM3 mice infused with CD19.28z CAR-T cells, two days after cytokine release syndrome (CRS) onset and 5 days later.

2018-05-24 | E-MTAB-6505 | biostudies-arrayexpress

B cell directed CAR-T cell therapy results in activation of CD8+ cytotoxic CAR-negative bystander T cells in both non-human primates and patients

Project description:There is growing appreciation for the emergence of CARneg bystander T cells after CAR-T cell infusion. However, their phenotypic and transcriptomic hallmarks and mechanisms of activation remain uncertain. We performed single-cell RNA-Seq (scRNA-Seq) on non-human primate (NHP) and patient-derived T cells to interrogate CARneg T cells following B cell targeted CAR-T cell therapy. In a NHP model, we observed a distinct population of activated CD8+ CARneg T cells emerging during CAR-T cell expansion. These bystander CD8+ CARneg T cells exhibited a unique transcriptional signature with upregulation of NK-cell markers (KIR3DL2, CD160, KLRD1), chemokines and chemokine receptors (CCL5, XCL1, CCR9), and downregulation of naive T cell-associated genes (SELL, CD28). A transcriptionally similar population was identified in patients following Tisangelecleucel infusion. Mechanistic studies revealed that IL-2 and IL-15 exposure induced bystander-like CD8+ T cells. These T cells efficiently killed leukemic cells through a TCR-independent mechanism. Together, these data identify bystander CD8+ T cells as a novel mechanism by which CAR-T cell infusion can induce further anti-leukemic activity, measurable in both NHP and in patients.

2024-04-05 | GSE245419 | GEO

B cell directed CAR-T cell therapy results in activation of CD8+ cytotoxic CAR-negative bystander T cells in both non-human primates and patients (human)

2024-05-05 | GSE266486 | GEO

Multi-Omic Single-Cell Dissection of Leukemic T-Cell Lymphoma Following CAR T-Cell Therapy [scRNA-seq]

Project description:Multi-Omic Single-Cell Dissection of Leukemic T-Cell Lymphoma Following CAR T-Cell Therapy [scRNA-seq]

| PRJNA1192233 | ENA

Multi-Omic Single-Cell Dissection of Leukemic T-Cell Lymphoma Following CAR T-Cell Therapy [Spatial Transcriptomics]

Project description:Multi-Omic Single-Cell Dissection of Leukemic T-Cell Lymphoma Following CAR T-Cell Therapy [Spatial Transcriptomics]

| PRJNA1192235 | ENA

CAR T cells inhibit B cell activating phosphorylation in their targets

Project description:Adoptive cell therapy, a subset of cancer immunotherapy, is collection of therapeutic approaches which aim to redirect the immune system by reprogramming patient T-cells to target antigenic molecules differentially and specifically expressed in certain cancers. One promising immunotherapy technique is CAR T-cell therapy, where cancer cells are targeted through the expression a chimeric antigen receptor (CAR), a synthetic trans- membrane receptor that functionally compensates for the T-cell receptor (TCR) but targets a tumor associated antigen on the cancer cell surface. While CAR T-cell therapy is promising with two clinically approved second-generation CARs (Kymriah and Yescarta), few studies have investigated the mechanism of signal propagation in T-cells and no studies have investigated the potential signaling response in the target cells. To gain further insight to CAR-based signaling, we stimulated third generation CD19 CAR-expressing Jurkat T-cells by co-culture with SILAC labeled CD19HI Raji B-cells and used two phosphoenrichment strategies coupled with liquid chromatography-tandem mass spec- trometry (LC-MS/MS) to detect and analyze global phosphorylation changes in both cell populations. Analysis of the phosphopeptides originating from the CD19-CAR T cells revealed an increase in many phosphorylation events necessary for canonical TCR signaling. We also observed for the first time a significant decrease in B-cell receptor- related phosphopeptide abundance in CD19HI Raji B-cells after co-culture with CD19-targetted CAR T-cells.

2022-01-28 | PXD028109 | Pride

Gene expression analysis of leukemic samples in C57BL6 mice

Project description:[original title] Gene expression analysis of leukemic samples derived from AF4-MLL- or AF4-MLL/MLL-AF4-transduced and transplanted hematopoietic stem/precursor cells in C57BL6 mice. We used microarrays to analyze the global gene expression in leukemic cells with three distinct immunophenotypes. We compared leukemic cells isolated from the bone marrow of diseased mice and compared these profiles with normal bone marrow.

2010-07-07 | E-GEOD-20519 | biostudies-arrayexpress

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