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Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL

ABSTRACT: We report 101,326 single cell transcriptomes and surface protein landscape from the Chimeric antigen receptor-modified (CAR) T infusion products of 12 pediatric ALL patients upon CAR antigen-specific stimulation in comparison with TCR-mediated activation and controls.

ORGANISM(S): Homo sapiens

PROVIDER: GSE197215 | GEO | 2022/06/08

REPOSITORIES: GEO

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Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL

Project description:Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL

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Targeted scRNA-seq and AbSeq of human CAR-T cell infusion product from 28 cancer patients

Project description:Immunotherapy using CD19-directed chimeric antigen receptor (CAR)-T cells has shown excellent results for treatment of B-cell leukaemia and lymphoma. To produce CAR-T cells, the patient’s own T cells are isolated from the blood and modified in a laboratory with a genetic vector to express a tumor antigen-directed CAR on its surface. The CAR-T cells are then expanded in numbers and given back to the patient with the aim to eradicate the tumors. However, some patients display primary resistance to CAR-T treatment while others relapse quickly after CAR-T treatment. In this experiment, we seek to understand whether the quality of the individual CAR-T cell product the patients were given can predict outcome to the therapy. We investigate the transcriptional profile of the individual CAR-T infusion products using single-cell RNA sequencing. In this dataset, we identified a T cell subset correlating with response that could be used as an indicator for clinical outcome. Targeted RNA and protein single-cell libraries were obtained using the BD Rhapsody platform (BD Biosciences). In total four separate targeted libraries were produced with 6 patients per library. Sequencing was performed on NovaSeq 6000 S1 sequencer at the SNP&SEQ Technology Platform (Uppsala, Sweden). The raw scRNA-seq data was pre-processed by BD Biosciences using the Rhapsody Analysis pipeline to convert the raw reads into Unique Molecular Identifier (UMI) counts. UMIs are further adjusted within Rhapsody by applying BD’s Recursive Substitution Error Correction (RSEC) and Distribution-Based Error Correction (DBEC) in order to remove false UMIs caused by sequencing or library preparation errors. Pooled samples were deconvoluted using Sample-tag reads. The scRNA-seq and AbSeq counts were loaded, processed and used for clustering and differential gene expression with Seurat v. 4.0.0.

2023-07-24 | E-MTAB-12407 | biostudies-arrayexpress

Single-cell antigen-specific landscape of CAR T infusion product identifies determinants of CD19-positive relapse in patients with ALL.

Project description:A notable number of acute lymphoblastic leukemia (ALL) patients develop CD19-positive relapse within 1 year after receiving chimeric antigen receptor (CAR) T cell therapy. It remains unclear if the long-term response is associated with the characteristics of CAR T cells in infusion products, hindering the identification of biomarkers to predict therapeutic outcomes. Here, we present 101,326 single-cell transcriptomes and surface protein landscape from the infusion products of 12 ALL patients. We observed substantial heterogeneity in the antigen-specific activation states, among which a deficiency of T helper 2 function was associated with CD19-positive relapse compared with durable responders (remission, >54 months). Proteomic data revealed that the frequency of early memory T cells, rather than activation or coinhibitory signatures, could distinguish the relapse. These findings were corroborated by independent functional profiling of 49 patients, and an integrative model was developed to predict the response. Our data unveil the molecular mechanisms that may inform strategies to boost specific T cell function to maintain long-term remission.

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Single-cell transcriptomics of chimeric antigen receptor (CAR) T cell infusion products

Project description:Adoptive immunotherapy with T cells expressing chimeric antigen receptors (CARs) for B-cell malignancies serves as a model for identifying subsets with superior clinical activity. We profiled the infusion products (IP) of 9 patients with large B-cell lymphoma (LBCL) using scRNA-sequencing to reveal the therapeutic potential of CD19-specific CAR+ T cells. ScRNA-seq demonstrated that T cells from responders were enriched in pathways related to T-cell killing, migration and actin cytoskeleton, and TCR clustering.

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Single-cell transcriptomics of chimeric antigen receptor (CAR) T cell infusion products

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Epigenetic profiling and response to CD19 chimeric antigen receptor (CAR) T-cell therapy in B-cell malignancies

Project description:Chimeric antigen receptor (CAR) T-cells directed against CD19 (CART19) are effective in relapsed/refractory (R/R) B-cell malignancies. Not all patients show treatment efficacy, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. Our objective was to determine the effect of epigenetic changes in CART19 cells on the clinical course of B-cell malignancy patients treated with adoptive therapy. We report a case series of B-cell malignancy patients (68 males (M) and 46 females (F); median age of 24 years (range 3-70 years)), comprising 77 acute lymphoblastic leukemia (ALL) cases and 37 non-Hodgkin lymphoma (NHL) cases, who were treated with CART19 cells. Using a DNA methylation microarray, we determined the epigenomic changes that occur in the patient T-cells upon transduction of the CAR vector. We identified 984 genomic sites with differential DNA methylation between CAR-untransduced (UT) and CAR-transduced (TD) T-cells before infusion into the patient. 18 of these distinct epigenetic loci were significantly associated with complete response (CR). Using the sites linked to CR, the EPICART signature was established, which was associated with enhanced overall survival (OS).

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Expression data from mouse CD19-targeted CAR (chimeric antigen receptor) T cells after antigen stimulation [RNA-seq]

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Expression data from mouse CD19-targeted CAR (chimeric antigen receptor) T cells after antigen stimulation [expression array]

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Single cell RNA sequencing of CD19 CAR T-cell infusion products

Project description:We performed single cell RNA sequencing of remnants from CD19 CAR T-cell infusion products used for standard of care treatment for relapsed/refractory large B-cell lymphoma. Libraries were prepared using 10X 5Ã¢Â€Â™ GEX chemistry and sequenced on an Illumina HiSeq 4000 to obtain >50,000 reads per cell.

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Clonal kinetics and single cell transcriptional profiling of adoptively transferred CD19-specific CD8+ CAR-T cells in adults with B cell malignancies

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

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