Gastrointestinal CAR T-cell Lymphoma after ciltacabtagene autoleucel
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE310992 | GEO | 2026/04/14
REPOSITORIES: GEO
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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.
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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
Project description:C.TNC-CAR.Zip18R CAR-T cell of 2 donors were used for 2 in vitro experiments. In the first experiment, we did scRNA-seq for activated CAR-T cells. In the second experiment, the CAR-T cells of each donor were cocultured with tumor cells for 12 hrs, 24 hrs and 48 hrs. The CAR-T cells for each timepoints were extracted for scRNA-seq. Multiplexed 10x Genomics scRNA-seq were performed with a hashtag to label each sample.
2024-11-20 | GSE282046 | GEO
Project description:Gastrointestinal CAR T-cell Lymphoma after ciltacabtagene autoleucel
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Project description:Purpose: To compare cell states between CD19-28z and GD2-28z human CAR T cells on day 10 of cell culture. Methods: Human T cells were activated and lentivirally transduced with CD19-28z or GD2-28z CAR constructs and maintained in culture for 10 days, and then delivered to the Stanford Functional Genomics Facility for 3' single-cell RNA-sequencing on the 10X Genomics platform. Results: Comparison of transcription factor profiles by single cell RNA-seq analysis of CD8+ T cells expressing CD19-28z vs. GD2-28z CAR confirmed that the bZIP family members JUN, JUNB, JUND, and ATF4 were among the most differentially expressed and broadly connected in exhausted GD2-28z CAR T cells. Conclusions: This study provides insights into cell states that could explain the underlying differences between highly functional CD19-28z CAR T cells and exhaustion-prone GD2-28z CAR T cells on day 10 in culture.
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Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
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Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
2026-05-31 | MTBLS14640 | MetaboLights
Project description:Chimeric antigen receptor (CAR) T cell therapies have revolutionized B cell malignancy treatment, but subsets of patients with large B cell lymphoma (LBCL) experience primary resistance or relapse after CAR T cell treatment. To uncover tumor microenvironment (TME)-induced resistance mechanisms, we examined patients’ intratumoral immune infiltrates and observed that elevated levels of immunoregulatory macrophages in pre-infusion tumor biopsies are correlated with poor clinical responses. In murine models, CAR T cell-produced interferon-gamma (IFN-g) promotes the expression of inducible nitric oxide synthase (iNOS, NOS2) in immunoregulatory macrophages, impairing CAR T cell function. Mechanistically, proteomics analysis of CAR T cells revealed that iNOS-expressing macrophages promote the upregulation of genes mediating apoptosis and cell cycle arrest in CAR T cells, while downregulating ribosome biogenesis and protein synthesis. Furthermore, CAR T cell metabolism is compromised by the depletion of glycolytic intermediates and rewiring of the TCA cycle. Pharmacological inhibition of iNOS enhances the CAR T cell treatment efficacy in B cell tumor-bearing mice. Notably, elevated levels of iNOS+CD14+ monocytes were observed in leukaphereses of patients with non-durable response to CAR T cell therapy. These findings suggest that mitigating iNOS in tumor-associated macrophages (TAMs), potentially by modulating IFN-g expression in CAR T cells, could improve outcomes for LBCL patients.
2026-05-30 | PXD079082 | Pride
Project description:Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients with high-risk features, such as MYCN aberrations, and relapsed/refractory disease have poor clinical outcomes. This underscores the urgent need for new therapies. Glypican-2 (GPC2) is a MYCN-regulated and recently discovered oncofetal antigen. Given that GPC2 is also expressed in brain tumors, we evaluated the preclinical activity of our GPC2-CAR (CT3-CD28HTM-BBζ) against MB and compared it to two existing CARs targeting GD2 and B7-H3. A newly generated patient-derived xenograft (PDX) MAF1433, with MYCN aberrations, were used to test CAR T-cells in vivo. Single-cell RNA-sequencing were used for mechanistic studies. MB patient samples express intermediate to high levels of GPC2 and can be targeted with a GPC2-CAR, leading to significant in vivo tumor regression in orthotopic tumor models. GPC2-CAR T-cells had equivalent activity to the B7-H3-CAR and enhanced activity compared to the GD2-CAR in vivo. T-cell kinetic studies revealed that GPC2-CAR T-cells home to the TME, expand, and upregulate genes critical for cytotoxicity and T-cell homing to induce MB cell death. CT3-CD28HTM-BBζ GPC2-CAR can regress GPC2+ MB with MYCN aberrations in preclinical studies, providing a preclinical rationale for including children with GPC2+ MB in our upcoming clinical GPC2-CAR T-cell trial.
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