Genome-wide chromatin accessibility profiles of TET2-disrupted T cells from a chronic lymphocytic leukemia (CLL) patient.
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE112494 | GEO | 2018/03/30
REPOSITORIES: GEO
Similar Datasets
Project description:Lymphodepletion chemotherapy followed by infusion of T cells modified to express a CD19-targeting chimeric antigen receptor (CAR) has produced remarkable anti-tumor responses in patients with B cell malignancies. However, little is known about the clonal composition and transcriptional heterogeneity of CAR-T cells in the infusion products (IP) and clonal kinetics after adoptive transfer. We performed single-cell RNA sequencing (scRNA-seq) on CD8+ CAR-T cells isolated from the IP and the blood of patients treated on a phase 1 clinical trial (NCT01865617) with lymphodepletion chemotherapy and a defined formulation of CD4+ and CD8+ CD19-specific CAR-T cells. Infused CD8+ CAR-T cells displayed transcriptional heterogeneity which declined after adoptive transfer, coincident with early expression of genes associated with activation. We identified four transcriptionally distinct CAR-T cell subsets in the IP and found that these subsets differed in their contributions to the CAR-T cell population detected in blood after infusion. Better understanding of the kinetics of clonal expansion of CAR-T cells after adoptive transfer may provide insight into strategies to improve CAR-T cell immunotherapy.
2019-11-22 | GSE125881 | GEO
Project description:Despite initial high-rates of complete response, <50% of B-cell acute lymphoblastic leukemia (B-ALL) patients treated with CD19-directed chimeric antigen receptor (CAR)-T cells maintain durable remissions. We integrated clonal kinetics and genetic heterogeneity with single-cell-TCR sequencing and single-cell-RNA sequencing, respectively, to explore the cellular dynamics response of both non-transduced (CARneg) and transduced (CARpos) T-cells. CARneg and CARpos T-cells were longitudinally interrogated in the manufactured infusion product (IP) and in peripheral blood at the time of CAR-T cell expansion peak following infusion in five adult B-ALL patients treated with CD19CAR-T products.
2024-01-27 | GSE235760 | GEO
Project description:Chimeric antigen receptor (CAR)-modified T-cells have become established as an effective treatment of haematological cancers. In the context of relapsed and refractory childhood pre-B cell acute lymphoblastic leukaemia (B ALL), CD19 targeting CAR T-cells often induce durable remissions. Previously, we generated a novel low-affinity CAR incorporating a CD19-specific single-chain variable fragment (scFV) called CAT, displaying a faster off-rate of interaction than the FMC63 CD19 binder used in prior clinical studies. Here, we systematically analysed CD19 CAR T-cells of ten children with relapsed or refractory B ALL enrolled in the CARPALL trial (NCT02443831). To characterize persisting CD19 CAR T-cells, we performed high throughput single-cell gene expression and T-cell receptor (TCR) sequencing of infusion products and serial blood and bone marrow samples up to five years post-infusion. We isolated CAR T-cells from peripheral blood or bone marrow by flow cytometry for CD3 and CAR expression, prior to single cell sequencing (Chromium 10X) platform.
| EGAD00001010018 | EGA
Project description:Adoptive transfer of chimeric antigen receptor (CAR)-T cells is expected to become the first line of treatment for multiple malignancies, following the enormous success of anti-CD19 therapies. However, their mechanism of action is not fully understood, and clear guidelines for the design of safe and efficient receptors are missing. We hereby describe a systematic analysis of the CAR “signalosome” in human primary T cells. Two CAR designs were compared: a second-generation (PSCA2) and a third-generation (PSCA3) anti-PSCA CAR. Phosphorylation events triggered by CAR-mediated recognition of target cells were quantified by mass spectrometry.
2019-11-07 | PXD007086 | Pride
Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 yielded remarkable outcomes in patients with acute lymphoblastic leukemia. To identify potential CAR targets in acute myeloid leukemia (AML), we probed the AML surfaceome for over-expressed molecules with potentially tolerable systemic expression. We integrated large transcriptomics and proteomics data sets from malignant and normal tissues, and developed an algorithm to identify potential targets expressed in leukemia stem cells, but not in normal CD34+CD38– hematopoietic cells, T cells or vital tissues. As these investigations did not uncover candidate targets with a profile as favorable as CD19, we developed a generalizable combinatorial targeting strategy fulfilling stringent efficacy and safety criteria. Our findings indicate that several target pairings hold great promise for CAR therapy of AML.
2017-10-24 | PXD007552 | Pride
Project description:<p>The adoptive transfer of autologous T cells genetically modified to express a CD19-specific, 4-1BB/CD3zeta-signaling chimeric antigen receptor (CAR; CTL019) has shown remarkable activity in patients with B acute lymphoblastic leukemia. Similar therapy can induce long-term remissions for relapsed/refractory chronic lymphocytic leukemia (CLL) patients, but in only a small subset of subjects. The determinants of response and resistance to CTL019 therapy of CLL are not fully understood. We employed next generation sequencing of RNA (RNA-seq) to identify predictive indicators of response to CTL019 treatment. We performed RNA-seq on leukapheresis and manufactured infusion product T cells from patients with heavily pre-treated and high-risk disease. To characterize potency, we also performed RNA-seq on the cellular infusion product after CAR-specific stimulation. Our findings indicate that durable remission in CLL is associated with gene expression signatures of early memory T cell differentiation (e.g., STAT3), while T cells from poorly- or non-responding patients exhibited elevated expression of key regulators of late memory as well as effector T cell differentiation, apoptosis, aerobic glycolysis, hypoxia and exhaustion. These gene expression signatures, along with additional immunological biomarkers, may be used to identify which patients are most likely to respond to cellular therapies and suggest manufacturing modifications that might potentiate the generation of maximally efficacious infusion products.</p>
| phs001707 | dbGaP
Project description:Chimeric antigen receptor T cell (CAR-T) targeting the CD19 antigen represents an innovative therapeutic approach to improve the outcome of relapsed or refractory B-cell acute lymphoblastic leukemia (B-ALL). Yet, despite a high initial remission rate, CAR-T therapy ultimately fails for some patients. Notably, around half of relapsing patients develop CD19 negative (CD19neg) B-ALL allowing leukemic cells to evade CD19-targeted therapy. Herein, we investigate leukemic cells of a relapsing B-ALL patient, at two-time points: before (T1) and after (T2) anti-CD19 CAR-T treatment. We show that at T2, the B-ALL relapse is CD19 negative due to the expression of a non-functional CD19 transcript retaining intron 2. Then, using single-cell RNA sequencing (scRNAseq) approach, we demonstrate that CD19neg leukemic cells were present before CAR-T cell therapy and thus that the relapse results from the selection of these rare CD19neg B-ALL clones. In conclusion, our study shows that scRNAseq profiling can reveal pre-existing CD19neg subclones, raising the possibility to assess the risk of targeted therapy failure.
2020-12-11 | GSE153697 | GEO
Project description:Chimeric antigen receptor (CAR) therapy targeting CD19 is an effective treatment for refractory B cell malignancies, especially acute lymphoblastic leukemia (ALL). While a majority of patients will achieve a complete response following a single infusion of CD19 CAR T cells, the broad applicability of this treatment is hampered by severe cytokine release syndrome (CRS), which is characterised by fever, hypotension and respiratory insufficiency associated with elevated serum cytokines including interleukin-6 (IL-6). CRS usually occurs within days of T cell infusion at the peak of CAR T cell expansion. In ALL, it is most frequent and more severe in patients with high tumour burden CRS is often responsive to IL-6 receptor blockade, but may require intensive life support and further treatment with high dose corticosteroids to prevent potentially lethal severity. Improved therapeutic and preventive treatments require a better understanding of CRS physiopathology, which has so far remained elusive. We report here a murine model of CRS that develops within 2-3 days of CAR T cell infusion, may be lethal and is responsive to IL-6 receptor blockade. We show that its severity is mediated not by CAR T cell-derived cytokines but by IL-6, interleukin-1 (IL-1) and Nitric Oxide (NO) produced by recipient macrophages. This CRS mechanism enables novel therapeutic interventions.
2018-05-28 | GSE111236 | GEO
Project description:<p>Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (r/r) large B-cell lymphoma (LBCL) results in durable response in only a subset of patients. MYC overexpression in LBCL tumors is associated with poor response to treatment. We tested whether a MYC-driven polyamine signature, as a liquid biopsy, is predictive of response to anti-CD19 CAR-T therapy in patients with r/r LBCL. Elevated plasma acetylated polyamines were associated with non-durable response. Concordantly, increased expression of spermidine synthase, a key enzyme which regulates levels of acetylated spermidine, was prognostic for survival in r/r LBCL. A broad metabolite screen identified additional markers which resulted in a 6-marker panel (6MetP) consisting of acetylspermidine, diacetylspermidine and lysophospholipids which was validated in an independent set from another institution as predictive of non-durable response to CAR T therapy. A polyamine centric metabolomics liquid biopsy panel has predictive value for response to CAR-T therapy in r/r LBCL. </p>
2022-10-31 | MTBLS5381 | MetaboLights
Project description:Single-cell RNA sequencing of PBMCs and infusion products from 32 patients treated with CD19 CAR-T therapy
2022-07-13 | GSE197268 | GEO