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Project description:We report the transcriptomic and epigentic profile of human primary CD19-28z CAR-T cells.
2022-09-06 | GSE174279 | GEO
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.
2019-10-01 | GSE136874 | GEO
Project description:In this data set we include expression data from human CD4+ T cells isolated on day 0, 6, 11 and 24 follow anti-CD3/anti-CD28 magnetic bead stimulation and chimeric antigen receptor transduction. 30 samples were submitted. Samples represented three biological replicates of normal donors transduced with various CARs. CARs used were a cMet 28z specific CAR comprised of the IgG4 hinge, CD28 transmembrane and CD28 and CD3zeta intracellular domains. A CD19 CD28 CAR was specific to CD19, and was comprised of a CD8a hinge, CD28 transmembrane and CD28 and CD3zeta intracellular domain. A third CAR, the CD19 BBz, was used that was specific to CD19 was comprised of a CD8a hinge, CD8a transmembrane and 4-1BB and CD3zeta intracellular domains. Expression data was analyzied on day 0, 6, 11 and 24.
2015-01-14 | E-GEOD-64914 | biostudies-arrayexpress
Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
2021-05-01 | GSE168880 | GEO
Project description:To characterize transfer of molecules from target cells into CAR T cells via trogocytosis we cultured NALM-6 leukemia cell line expressing a CD19-mCherry fusion protein with CAR T cells. NALM6-CD19-mCherry were loaded with heavy amino acid and cocultured with CAR T cells for 1 hour. CAR T cells were next sorted into two fractions, mCherry-positive (TrogPos), and -negative (TrogNeg). Proteomics analysis revealed the presence of targeted antigen (CD19) in the TrogPos only.
2019-03-29 | PXD012833 | Pride
Project description:The production of autologous T cells expressing a chimaeric antigen receptor (CAR) is time-consuming, costly and occasionally unsuccessful. T cell-derived induced pluripotent stem cells are a promising source for the generation of ‘off-the-shelf’ CAR T cells, but their in vitro differentiation often yields T cells with suboptimal features. Here we show that premature expression of the T cell receptor (TCR) or a constitutively expressed CAR promote the acquisition of an innate phenotype, which can be averted by disabling the TCR and relying on the CAR to drive T cell differentiation. Delaying CAR expression and calibrating its signalling strength enabled the generation of human CD8αβ+ TCR– CAR+ T cells that perform overall similarly to peripheral blood CD8αβ+ CAR+ T cells in achieving effective tumour control upon systemic administration in a mouse model of leukaemia, without causing graft-versus-host disease. Driving T cell maturation in the absence of a TCR by taking advantage of a CAR may facilitate the large-scale development of potent allogeneic CD8αβ+ T cells for a broad range of immunotherapies. TRAC-1XX-iT cell generation: TiPS were differentiated to the DP T cell stage, and matured to CD8ab SP cells on 3T3-CD19-41BBL. CD8ab SP cells were purified by flow cytometry. Peripheral Blood Mononuclear cells were purified from healthy donor whole blood. CD4 and CD8 T cells were targeted with CD19-28z-1XX CAR into the TRAC locus, NK and gdT cells were retrovirally transduced to express the CD19-28z-1XX CAR. Cells were purified for CAR expression by flow cytometry.
2022-08-23 | GSE210364 | GEO
Project description:Dysfunction in T cells limits the efficacy of cancer immunotherapy. We profiled the epigenome, transcriptome, and enhancer connectome of exhaustion-prone GD2-targeting HA-28z chimeric antigen receptor (CAR) T cells and control CD19-targeting CAR T cells, which present less exhaustion-inducing tonic signaling, at multiple points during their ex vivo expansion. We found widespread, dynamic changes in chromatin accessibility and 3D chromosome conformation preceding changes in gene expression, notably at loci proximal to exhaustion-associated genes such as PDCD1, CTLA4, and HAVCR2, and increased DNA motif access for AP-1 family transcription factors, which are known to promote exhaustion. Although T cell exhaustion has been studied in detail in mouse, we find that the regulatory networks of T cell exhaustion differ between the species and involve distinct loci of accessible chromatin and cis-regulated target genes in human CAR T cell exhaustion. Deletion of exhaustion-specific candidate enhancers of PDCD1 suppress the expression of PD-1 in an in vitro model of T cell dysfunction and in HA-28z CAR T cells, suggesting enhancer editing as a path forward in improving cancer immunotherapy.
2021-05-01 | GSE168881 | GEO
Project description:Adoptive cell therapy, a subset of cancer immunotherapy, is collection of therapeutic approaches which aim to redirect the immune system by reprogramming patient T-cells to target antigenic molecules differentially and specifically expressed in certain cancers. One promising immunotherapy technique is CAR T-cell therapy, where cancer cells are targeted through the expression a chimeric antigen receptor (CAR), a synthetic trans- membrane receptor that functionally compensates for the T-cell receptor (TCR) but targets a tumor associated antigen on the cancer cell surface. While CAR T-cell therapy is promising with two clinically approved second-generation CARs (Kymriah and Yescarta), few studies have investigated the mechanism of signal propagation in T-cells and no studies have investigated the potential signaling response in the target cells. To gain further insight to CAR-based signaling, we stimulated third generation CD19 CAR-expressing Jurkat T-cells by co-culture with SILAC labeled CD19HI Raji B-cells and used two phosphoenrichment strategies coupled with liquid chromatography-tandem mass spec- trometry (LC-MS/MS) to detect and analyze global phosphorylation changes in both cell populations. Analysis of the phosphopeptides originating from the CD19-CAR T cells revealed an increase in many phosphorylation events necessary for canonical TCR signaling. We also observed for the first time a significant decrease in B-cell receptor- related phosphopeptide abundance in CD19HI Raji B-cells after co-culture with CD19-targetted CAR T-cells.
2022-01-28 | PXD028109 | Pride
Project description:The tumor microenvironment presents many obstacles to effective CAR T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Ra2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes Tscm formation and prolongs survival. RNA sequencing of these CAR T cells reveals that overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR T cells improve tumor control and response to rechallenge in an RCC patient derived xenograft model. Furthermore, IL13Ra2-BBz CAR T cells overexpressing GLUT1 prolong survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR T cells in harsh tumor environments where glucose is limiting.
2024-05-30 | GSE265904 | GEO
Project description:Genome-wide maps of chromatin state in human primary CAR-T cells [ChIPseq, ATAC-seq]
| PRJNA729086 | ENA