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Homo sapiens

ABSTRACT: Resistance to HER2-TCB (T cell bispecfic) and -CAR (chimeric antigen receptor) through JAK2 downmodulation

PROVIDER: PRJNA674313 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13071461_1.fastq.gz	Fastqsanger.gz
	SRR13071461_2.fastq.gz	Fastqsanger.gz
	SRR13071462_1.fastq.gz	Fastqsanger.gz
	SRR13071462_2.fastq.gz	Fastqsanger.gz
	SRR13071463_1.fastq.gz	Fastqsanger.gz

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Homo sapiens

Project description:Resistance to HER2-TCB (T cell bispecfic) and -CAR (chimeric antigen receptor) through JAK2 downmodulation

| PRJNA674036 | ENA

A Clinical Research of CAR T Cells Targeting HER2 Positive Cancer

Project description:Chimeric antigen receptor T cells (CAR-T) therapy has not yet been fully explored in solid tumors. Human epidermal growth factor receptor-2(HER2) is widely expressed in cancers. Investigators have developed anti-HER2 CAR-modified T cells and validated the efficiency targeting HER2-positive cancer in preclinical studies. This study is aimed to confirm its adverse effects including cytokine storm response and any other adverse effects. In addition, CAR-T cells persistence, tumor elimination and disease status after treatment will be evaluated.

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Single cell multi-omic dissection of response and resistance to chimeric antigen receptor T cells against BCMA in relapsed multiple myeloma

Project description:Markers predicting response and resistance to chimeric antigen receptor (CAR) T cells in relapsed/refractory multiple myeloma are currently missing. We subjected cells isolated from peripheral blood and bone marrow before and after the application of CAR T cells directed against B cell maturation antigen to single cell multi-omic analyses to identify markers associated with resistance and early relapse.

2023-12-15 | GSE234261 | GEO

Synergically enhanced anti-tumor immunity of in vivo CAR by vaccination-elicited antibody-mediated cellular cytotoxicity boosting

Project description:Chimeric Antigen Receptor (CAR) T cell therapy has shown promise in treating hematologic malignancies. However, it is limited to individualized cell therapy and faces challenges, including high costs, extended preparation time, and limited efficacy against solid tumors. Here, we generated circular RNAs (circRNAs) encoding Chimeric Antigen Receptor (CAR) transmembrane proteins, referred to as circRNACAR, which mediated remarkable tumor killing in both T cells and macrophages. In addition, macrophages exhibited efficient phagocytosis of tumor cells and pro-inflammatory polarization induced by circRNACAR in vitro. We demonstrated that circRNACAR, delivered with immunocyte-tropic lipid nanoparticles (LNPs), significantly inhibited tumor growth, improved survival rates and induced a pro-inflammatory tumor microenvironment in mice. Importantly, the combination of circRNAAnti-HER2-CAR and circRNA-based cancer vaccines encoding the corresponding transmembrane HER2 antigen, termed circRNAHER2, exhibited synergistically enhanced anti-tumor activity. Notably, we found that circRNACAR could boost the level of circRNAHER2-elicited antibodies, which could mediate effective killing of HER2+ tumor cells by macrophages, indicating the potential of vaccination-elicited antibodies in developing novel immunotherapy. This proof-of-concept study demonstrated that the combination of circRNA-based in vivo CAR and vaccines, termed in vivo CAR-VAC, holds the potential to become an upgraded off-the-shelf immunotherapy, and also sheds light on the huge potential of vaccination-elicited antibodies in cancer immunotherapy.

2024-05-22 | GSE268105 | GEO

Chaudhury2020 - Lotka-Volterra mathematical model of CAR-T cell and tumour kinetics

Project description:This ordinary differential equation model of the cellular kinetics and pharmacodynamics of CAR-T cell therapy is described in the publication: Chaudhury, A., Zhu, X., Chu, L., Goliaei, A., June, C., Kearns, J. and Stein, A., 2020. Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic‐Pharmacodynamic Modeling Approaches. The Journal of Clinical Pharmacology, 60(S1). DOI: 10.1002/jcph.1691 Comment: This model is based on equations 4-5 from the manuscript. Abstract: Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity.

2024-09-02 | BIOMD0000001024 | BioModels

Chaudhury2020 - EC50 expansion and killing mathematical model of CAR-T cell and tumour kinetics

Project description:This ordinary differential equation model of the cellular kinetics and pharmacodynamics of CAR-T cell therapy is described in the publication: Chaudhury, A., Zhu, X., Chu, L., Goliaei, A., June, C., Kearns, J. and Stein, A., 2020. Chimeric Antigen Receptor T Cell Therapies: A Review of Cellular Kinetic‐Pharmacodynamic Modeling Approaches. The Journal of Clinical Pharmacology, 60(S1). DOI: 10.1002/jcph.1691 Comment: This model is based on equations 7-9 from the manuscript. Abstract: Chimeric antigen receptor T cell (CAR-T cell) therapies have shown significant efficacy in CD19+ leukemias and lymphomas. There remain many challenges and questions for improving next-generation CAR-T cell therapies, and mathematical modeling of CAR-T cells may play a role in supporting further development. In this review, we introduce a mathematical modeling taxonomy for a set of relatively simple cellular kinetic-pharmacodynamic models that describe the in vivo dynamics of CAR-T cell and their interactions with cancer cells. We then discuss potential extensions of this model to include target binding, tumor distribution, cytokine-release syndrome, immunophenotype differentiation, and genotypic heterogeneity.

2024-09-02 | BIOMD0000001025 | BioModels

NR4a knock-down in HER2 CAR-T cells improves T cell longevity and promotes solid tumor eradication [RNA-Seq]

Project description:Chimeric antigen receptor (CAR)-T cell therapy targeting human CD19 have demonstrated clinical efficacy against B-cell malignancies. However, CAR-T cell therapy's efficacy against solid tumors is limited due to factors like low tumor-associated antigens, infiltration rate, and T cell exhaustion. We have shown that deleting NR4a genes in CAR-T cells prevents T cell exhaustion and improved their therapeutic effects on solid tumors in a mouse model. To further explore this for human, we deleted all three NR4a family factors in CAR-T cells that recognize Epidermal Growth Factor Receptor type 2 (HER2) using the CRISPR/Cas9 system. These modified CAR-T cells (NR4a-TKO CAR-T) exhibited resistance to exhaustion, increased tumor-killing activity, and higher efficacy in tumor regression and survival rate in a human lung carcinoma model in mice. The enhanced therapeutic effects were associated with increased cytokine expression, reduced exhaustion-related gene expression, and improved persistence within tumors. We propose that targeting NR4a could be a promising strategy for developing superior CAR-T cells against solid tumors.

2024-08-28 | GSE241456 | GEO

Biallelic loss of BCMA as a resistance mechanism to CAR T cell therapy in a patient with Multiple Myeloma

Project description:BCMA targeting chimeric antigen receptor (CAR) T cell therapy have shown deep and durable responses in multiple myeloma. However, relapse following therapy is frequently observed, and mechanisms of resistance remain ill-defined. We performed single cell genomic characterization of longitudinal samples from a patient who relapsed after initial CAR T cell treatment with lack of response to retreatment.

2021-01-11 | GSE164551 | GEO

Genome-wide chromatin accessibility profiles of TET2-disrupted T cells from a chronic lymphocytic leukemia (CLL) patient.

Project description:Following CD19-directed chimeric antigen receptor (CAR) T cell infusion, TET2 disrupted CAR+ T cells exhibited an epigenetic profile consistent with altered differentiation.

2018-03-30 | GSE112494 | GEO

Gene expression profiles of CD4-derived (CAR4) and CD8-derived (CAR8) chimeric antigen receptor T cells after stimulation through the CAR, TCR or both receptors

Project description:Chimeric antigen receptor (CAR)-expressing T-cells induce durable remissions in patients with relapsed/refractory B-cell malignancies. CARs are artificial constructs introduced into mature T-cells conferring a second, non-MHC restricted specificity in addition to the endogenous T-cell receptor (TCR). The impact of TCR activation on CAR T-cell efficacy in vivo has important implications for clinical optimization of CAR T-cell therapy, but cannot be systematically evaluated in xenograft models. Using an immunocompetent, syngeneic murine model of CD19-targeted CAR T-cell therapy for pre-B cell ALL, we demonstrate loss of CD8 CAR T-cell mediated clearance of leukemia associated with T-cell exhaustion and apoptosis when TCR antigen is present. CD4 CAR T-cells demonstrate equivalent cytotoxicity, as compared to CD8 CAR T-cells, and in contrast, retain in vivo efficacy in the presence of TCR stimulation. Gene expression profiles confirm increased exhaustion and apoptosis of CAR8 upon dual receptor stimulation compared to CAR4, and indicate inherent differences in T-cell pathways. Chimeric antigen receptor (CAR) T cells express two activating receptors, the CAR and the endogenous T cell receptor (TCR). CAR T cells can be derived from either CD8 or CD4 T cells to generate CAR8 and CAR4 cells, respectively. In vivo, CAR8 and CAR4 cells respond differently when simultaneously stimulated through the CAR and TCR.

2017-12-31 | GSE103632 | GEO

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