Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Optimized delivery of dual co-stimulation and anti-tumor activity using parallel chimeric antigen receptors (pCARs)

ABSTRACT: Second generation (2G) chimeric antigen receptors (CARs) contain a CD28 or 41BB co-stimulatory endodomain and elicit remarkable efficacy in hematological malignancies. Third generation (3G) CARs extend this linear blueprint by fusing both co-stimulatory units in series. However, clinical impact has been muted despite compelling evidence that co-signaling by CD28 and 41BB can powerfully amplify natural immune responses. We postulate that effective dual co-stimulation requires juxta-membrane positioning of endodomain components within separate synthetic receptors. Consequently, we designed parallel (p)CARs in which a 2G (CD28+CD3) CAR is co-expressed with a 41BB-containing chimeric co-stimulatory receptor. We demonstrate that the pCAR platform optimally harnesses synergistic and tumor-dependent co-stimulation to resist T-cell exhaustion and senescence, sustaining proliferation, cytokine release, cytokine signaling and metabolic fitness upon repeated stimulation. When engineered using targeting moieties of diverse composition, affinity and specificity, pCAR T-cells consistently elicit superior anti-tumor activity both in vitro and in vivo, warranting clinical development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE186557 | GEO | 2021/12/10

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Chimeric Antigen Receptors with a MyD88 and CD40 costimulatory endodomain endow T cells with superior antitumor activity

Project description:CAR T-cell therapy for solid tumors has shown limited efficacy in early phase clinical studies. The majority of CARs encode CD28 and/or 41BB costimulatory endodomains and we explored here if MyD88 and CD40 (MC) costimulatory endodomains in CARs improve their antitumor activity. We generated CD28-, 41BB-, and MC-CAR T-cells and demonstrate that MC-CAR T-cells have greater proliferative capacity and antitumor activity in repeat stimulation assays and in tumor models in vivo. Transcriptomic analysis revealed that MC-CAR T-cells expressed higher levels of MYB and FOXM1, key cell cycle regulators, and are activated at base line. After stimulation, MC-CAR T-cells remain in a less differentiated state than CD28- and 41BB-CAR T-cells as judged by low levels of TBET and BLIMP1 expression, and lower cytolytic activity in comparison to CD28- and 41BB-CAR T-cells. Thus, including MyD88 and CD40 signaling domains in CARs may improve current CAR T-cell therapy approaches for solid tumors.

2020-09-18 | GSE158144 | GEO

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

Project description:Second-generation CD19-targeted chimeric antigen receptors (CAR) have an antigen-binding domain fused to transmembrane, co-stimulatory, and CD3ζ domains. The two CARs with regulatory approval include a CD28 or 4-1BB co-stimulatory domain. While both CARs achieve similar clinical outcomes, biologic differences between the two endodomains have become apparent but not completely understood. The objective is to evaluate gene expression in different mouse CD19-targeted CAR T cells, including m19z, m1928z and m19-humBBz.

2018-07-31 | GSE112566 | GEO

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

2018-07-31 | GSE111641 | GEO

Costimulatory domains direct distinct fates of CAR-driven T cell dysfunction [ATAC-seq]

Project description:Chimeric antigen receptor (CAR) engineered T cells often fail to enact effector functions after infusion into patients. Understanding the biological pathways that lead CAR T cells to failure is of critical importance in the design of more effective therapies. We developed and validated an in vitro model that drives T cell dysfunction by chronic CAR stimulation and interrogated how CAR costimulatory domains contribute to T cell failure. We found that dysfunctional CD28-based CARs targeting CD19 bear hallmarks of classical T cell exhaustion while dysfunctional 41BB-based CARs are phenotypically, transcriptionally and epigenetically distinct. We confirmed activation of this unique transcriptional program in CAR T cells that failed to control clinical disease. Further, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is a significant contributor to this dysfunction and disruption of FOXO3 significantly improves 41BB-based CAR T cell function. These findings identify that chronic activation of 41BB leads to novel state of T cell dysfunction that can be alleviated by genetic modification of FOXO3.

2023-05-02 | GSE231309 | GEO

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [scRNA-seq]

2023-05-02 | GSE231311 | GEO

Costimulatory domains direct distinct fates of CAR-drivenT cell dysfunction [RNA-seq]

2023-05-02 | GSE231310 | GEO

Expression data from chimeric antigen receptor transduced (CAR) human CD4+ T cells during expansion

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

Optimization of CAR T cell signaling by incorporation of null mutations

Project description:An obstacle with continued clinical development of CAR T cells is the limited understanding of CAR T cell biology and its mechanisms of anti-tumor immunity. We and others have shown that CARs with a CD28 co-stimulatory domain drive high levels of T cell activation that also lead to exhaustion and shortened persistence. This led us to hypothesize that by incorporating null mutations of CD28 subdomains (YMNM, PRRP, or PYAP) we could optimize CAR T cell signaling and reduce exhaustion. In vivo we found that mice given CAR T cells with a PYAP CD28 endodomain had a significant survival advantage. We also observed that mutant CAR T cells had significantly less expression of PD1 and were increased in the bone marrow and spleen. In addition, these mutant CAR T cells had optimized signaling resulting in a reduction of exhaustion related transcription factors and genes. Our results demonstrate that CAR T cells with a mutant CD28 endodomain have better survival and decreased exhaustion and is the result of decreased CAR dependent NFAT/NR4A1 transcription factors. This work allows for development of enhanced CAR T cell therapies by optimizing CAR T cell signaling.

2020-12-16 | GSE142506 | GEO

Global phosphoproteomic analysis of signaling by distinct chimeric antigen receptors reveals kinetic and quantitative differences that influence cell function

Project description:Chimeric antigen receptors (CARs) are synthetic proteins that redirect T cell specificity by linking an extracellular ligand binding domain to intracellular T cell signaling domains. CAR-expressing T (CAR-T) cells have demonstrated significant efficacy for the treatment of refractory B cell malignancies and are being evaluated as immunotherapeutic reagents for many other cancers. CAR designs are based on the fundamental principles of TCR recognition and most CARs employ the T cell-activating CD3z endodomain alongside a costimulatory domain from CD28 or 4-1BB. However, emerging data suggest that CD28/CD3z and 4-1BB/CD3z signaling modules promote divergent metabolic pathways, gene expression programs, and cell fates. To determine how CAR phosphoprotein signaling drives these disparate cell fates, we analyzed CAR ligation-induced signaling networks in primary human T cells using shotgun mass spectrometry. We isolated CD8+CD62L+ T cells from healthy donors and introduced a CD28/CD3z or 4-1BB/CD3z CAR by lentiviral transduction. Transduced T cells were purified by FACS and expanded once in vitro. When the cells returned to a resting state, CD28/CD3z or 4-1BB/CD3z CAR-T cells were stimulated for 10 or 45 minutes with magnetic microbeads coated with a monoclonal antibody specific for a 9 amino acid tag in the CAR extracellular sequence. CAR-T cells were also left unstimulated for 10 or 45 minutes to serve as controls. Altogether, 8 unique conditions were tested in an experiment and three independent experiments were performed.

2018-08-13 | PXD007921 | Pride

Gene expression profile of TBBR modified T cells compared to control ΔTGFbRII T cells

Project description:The objective of this experiment was to compare the transcriptional profile of TBBR (TGFbRII ectodomain fused to 41BB endodomain) vs control ΔTGFbRII (truncated version that lacks an endodomain) modified T cells. RNA samples were isolated from trangenic T cells generated from three independent donors.

2018-04-20 | GSE113388 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data