A single cell atlas of CD19 chimeric antigen receptor T cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE241783 | GEO | 2023/08/29
REPOSITORIES: GEO
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Project description:Axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for treatment of relapsed/refractory large B-cell lymphoma (LBCL), has comparable efficacy across conventional LBCL markers. We analysed whether pre- and posttreatment tumour immune contexture determines clinical outcomes for axi cel–treated patients in the ZUMA-1 pivotal study. Longitudinal evaluation of the tumour microenvironment (TME) uncovered dynamic patterns that occurred rapidly after axi-cel (within 2 weeks) in responders—pronounced enhancement of T- and myeloid cell signatures and diminution of B cell signature. Clinical response and overall survival associated with high CD8+ T-cell density (Immunoscore) and immune gene expression (Immunosign21) in TME pretreatment, which was paralleled by blood CAR T-cell levels posttreatment. High density of regulatory T cells in TME pretreatment associated with reduced axi-cel–related neurologic toxicity. At relapse, the TME evolved toward an immune-detrimental contexture with decreased T-cell–related and increased counterregulatory immune signatures and B cell lineage antigens. A TME rich in T-cell attractive chemokines (CCL5, CCL22), gamma-chain receptor cytokines (IL-15, IL-7, IL-21), and interferon regulated molecules associated with T-cell infiltration and markers of activity, a result validated in 2 independent datasets totalling ≈300 LBCL samples. These findings advance mechanistic understanding of CAR T-cell therapy and foster biomarker development and treatment optimizations.
2022-09-23 | GSE197977 | GEO
Project description:The phase 3 ZUMA-7 trial in second-line large B-cell lymphoma demonstrated superiority of anti-CD19 CAR T-cell therapy (axicabtagene ciloleucel; axi-cel) over standard of care (SOC; salvage chemotherapy followed by hematopoietic transplantation). Here, we present a prespecified exploratory analysis examining the association between pretreatment tumor characteristics and the efficacy of axi-cel versus SOC. B-cell gene expression signature (GES) and CD19 expression significantly associated with improved event-free survival (EFS) for axi-cel (P=.0002 for B-cell GES; P=.0165 for CD19 expression) but not SOC (P=.9374 for B-cell GES; P=.5526 for CD19 expression). Axi-cel showed superior EFS over SOC irrespective of B-cell GES and CD19 expression (P=8.56e–9 for B-cell GES high; P=.0019 for B-cell GES low; P=3.85e–9 for CD19 gene high; P=.0017 for CD19 gene low). Low CD19 expression in malignant cells correlated with a tumor GES consisting of immune suppressive stromal and myeloid genes, highlighting the inter-relation between malignant cell features and immune contexture substantially impacting axi-cel outcomes. Tumor burden, lactate dehydrogenase, and cell-of-origin impacted SOC more than axi-cel outcomes. T-cell activation and B-cell GES, which are associated with improved axi-cel outcome, decreased with increasing lines of therapy. These data highlight differences in resistance mechanisms to axi-cel and SOC and support earlier intervention with axi-cel.
2024-02-26 | GSE248835 | GEO
Project description:Engineered cellular therapy with CD19-targeting chimeric antigen receptor T-cells (CAR-T) has revolutionized outcomes for patients with relapsed/refractory Large B-Cell Lymphoma (LBCL), but the cellular and molecular features associated with response remain largely unresolved. We analyzed serial peripheral blood samples ranging from day of apheresis (day -28/baseline) to 28 days after CAR-T infusion from 50 patients with LBCL treated with axicabtagene ciloleucel (axi-cel) by integrating single cell RNA and TCR sequencing (scRNA-seq/scTCR-seq), flow cytometry, and mass cytometry (CyTOF) to characterize features associated with response to CAR-T. Pretreatment patient characteristics associated with response included presence of B cells and increased lymphocyte-to-monocyte ratio (ALC/AMC). Infusion products from responders were enriched for clonally expanded, highly activated CD8+ T cells. We expanded these observations to 99 patients from the ZUMA-1 cohort and identified a subset of patients with elevated baseline B cells, 80% of whom were complete responders. We integrated B cell proportion and ALC/AMC into a two-factor predictive model and applied this model to the ZUMA-1 cohort. Estimated progression free survival (PFS) at 1 year in patients meeting one or both criteria was 65% versus 31% for patients meeting neither criterion. Our results suggest that patients’ immunologic state at baseline affects likelihood of response to CAR-T through both modulation of the T cell apheresis product composition and promoting a more favorable circulating immune compartment prior to therapy. These baseline immunologic features, measured readily in the clinical setting prior to CAR-T, can be applied to predict response to therapy.
2024-08-12 | GSE273170 | GEO
Project description:Purpose: To compare cell states amoung three populations of interest among circulating CAR T cells in patients with lymphoma. Methods: Nine patients with large B-cell lymphoma (LBCL) were treated with axicabtagene ciloleucel (axi-cel), a commercial CD19-targeted CAR T-cell therapy. On day 7, fresh peripheral blood mononuclear cells were stained with an antibody panel for fluorescence-activated cell sorting (FACS), a panel for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq), and a viability dye. Single live CAR+ T cells were sorted from each patient, counted, processed for 5' single-cell RNA-sequencing with feature barcoding and TCR clonotype analysis on the 10X Genomics platform, and sequenced by the Stanford Genomics Facility (HighSeq 4000) or Novogene (NovaSeq 6000). Results: We found that circulating CD4+ and CD8+ CAR T cells that express CD57 and T-bet are clonally expanded and display features of effector T cells. In contrast, CD4+ CD57- CAR T cells that express Helios expand polyclonally and display features of T regulatory cells. Conclusions: This study provides insights into cell states of circulating CAR T cells on day 7 that associate with clinical response or toxicity in LBCL patients treated with axi-cel.
2022-07-28 | GSE168940 | GEO
Project description:CD19-directed chimeric antigen receptor (CAR) T cells can induce durable remissions in relapsed/refractory large B-cell lymphomas (R/R LBCL), but 60% of patients still relapse. Biological mechanisms explaining lack of disease-response are largely unknown. To identify mechanisms of response and survival before CAR T manufacturing in 95 R/R LBCL receiving tisagenlecleucel or axicabtagene ciloleucel, we performed phenotypic, transcriptomic and functional evaluations of leukapheresis products (LK). Transcriptomic profiling of T cells in LK, revealed a signature composed of 4 myeloid genes able to identify patients with very short progression-free survival, highlighting the role of monocytes in CAR T therapy response. Accordingly, response and survival were negatively influenced by high circulating absolute monocyte counts at the time of leukapheresis, and the combined evaluation of peripheral blood monocytes and the four-gene signature in LK, identifies LBCL patients at very high risk of progression after CAR T.
2024-04-24 | GSE243973 | GEO
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).
2021-08-23 | GSE179414 | GEO
Project description:We successfully developed a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. In the adoptive therapy for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, we observed durable responses without serious adverse events and complete remission in patients treated with PD1 knockin CAR T cells. Here we applied single-cell sequencing to analyze the characteristcis of infusion products and T cells after administration.
2022-06-20 | GSE166352 | GEO
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 5’ GEX chemistry and sequenced on an Illumina HiSeq 4000 to obtain >50,000 reads per cell.
| EGAS00001004576 | EGA
Project description:Despite remarkable progress in B cell malignancies, T cells expressing chimeric antigen receptors (CARs) remain ineffective in solid tumors in part because T cells do not traffic effectively to or survive in tumor tissues. We engineered Vα24-invariant natural killer T cells (NKTs), which intrinsically home to tumor sites, to co-express a GD2-specific CAR with interleukin (IL)15 and evaluated their therapeutic efficacy in children with relapsed/resistant neuroblastoma (NB)(NCT03294954). The first three patients received a single infusion of 3x10e6 autologous CAR-NKTs per square meter of body surface area and tolerated the treatment well. CAR-NKTs expanded in vivo, localized to the tumor, and in one patient induced a near-complete regression of bone metastatic lesions.
2020-08-10 | GSE154037 | GEO