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CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

ABSTRACT: CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

PROVIDER: PRJNA744919 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15075388_1.fastq.gz	Fastqsanger.gz
	SRR15075388_2.fastq.gz	Fastqsanger.gz
	SRR15075389_1.fastq.gz	Fastqsanger.gz
	SRR15075389_2.fastq.gz	Fastqsanger.gz
	SRR15075390_1.fastq.gz	Fastqsanger.gz

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CARPOOL: A library-based platform to rapidly identify next generation chimeric antigen receptors

Project description:CD19-targeted CAR therapies have successfully treated B cell leukemias, but many responders later relapse or experience toxicities. CAR ICDs are key to converting antigen recognition into anti-tumor effector functions. Despite the many possible immune signaling domain combinations that could be included in CARs, almost all CARs currently rely upon CD3, CD28, and/or 4-1BB signaling. To explore the signaling potential of CAR ICDs, we generated a library of 700,000 CD19 CAR molecules with diverse signaling domains and developed a high throughput screening platform to enable optimization of CAR signaling for anti-tumor functions. Our strategy identifies CARs with novel signaling domains that elicit distinct T cell behaviors from a clinically available CAR, including enhanced proliferation and persistence, lower exhaustion, potent cytotoxicity in an in vitro tumor rechallenge condition, and comparable tumor control in vivo. This approach is readily adaptable to numerous disease models, cell types, and selection conditions, making it a promising tool for rapidly improving adoptive cell therapies and expanding their utility to new disease indications.

2021-07-13 | GSE179767 | GEO

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

Project description: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.

2021-12-10 | GSE186557 | GEO

Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

Project description:Tonic-signaling chimeric antigen receptors drive human regulatory T cell exhaustion

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Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

Project description:Synthetic activation of chimeric EGFR-Erbb2 receptors causes nuclear translocation of the heterodimers at long time scales. To identify genomic loci bound by nuclear EGFR-Erbb2, chromatin from an MCF10A-5E clone coexpressing chimeric EGFR and Erbb2 was prepared with or without synthetic activation and immunoprecipitated for chimeric EGFR by its GluGlu epitope tag.

2023-03-22 | GSE216242 | GEO

Comparison of Transcriptional Profiles of T cells after Activation by TCR and Chimeric Antigen Receptors

Project description:Chimeric antigen receptor T (CAR-T) cell therapies for B cell malignancies demonstrate high response rate and durable disease control. However, in the case of solid tumors, CAR-T cells have shown dysfunction ascribed to some intrinsic defects in CAR signaling. Here, we construct a multi-chain chimeric receptor, termed as Synthetic T Cell Receptor and Antigen Receptor (STAR), which incorporates antigen-recognition domain of antibody and engages entire CD3 signaling machinery of T cell receptor (TCR). In multiple solid tumor models, STAR-T cells prominently outperform CAR-T cells without notable toxicity. STAR triggers strong and sensitive TCR-like signaling upon antigen stimulation. We compared the transcriptional profiles of STAR/CAR/TCR-T cells after stimulation for different time points (0, 6, 24, 72 hours), in order to figure out whether signaling difference of these receptors led to distinct gene expression. Our results showd that STAR activation phencopied TCR, while CAR drove a different program, displayed as various pathways related to effector function, cytokine response and cell survival were altered.

2021-02-14 | GSE160311 | GEO

Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

Project description:Chimeric EGFR ChIP-seq of an MCF-10A clone expressing chimeric EGFR and Erbb2 receptors

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CSE1L and NUP37 proximity labeling in MCF10A cells expressing chimeric ErbB1:ErbB2 receptors

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2023-03-22 | PXD038327 | Pride

Comparison of Transcriptional Profiles of T cells after Activation by TCR and Chimeric Antigen Receptors

Project description:Comparison of Transcriptional Profiles of T cells after Activation by TCR and Chimeric Antigen Receptors

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Chimeric Antigen Receptor Library Screening Using a Novel NF-κB/NFAT Reporter Cell Platform.

Project description:Chimeric antigen receptor (CAR)-T cell immunotherapy is under intense preclinical and clinical investigation, and it involves a rapidly increasing portfolio of novel target antigens and CAR designs. We established a platform that enables rapid and high-throughput CAR-screening campaigns with reporter cells derived from the T cell lymphoma line Jurkat. Reporter cells were equipped with nuclear factor κB (NF-κB) and nuclear factor of activated T cells (NFAT) reporter genes that generate a duplex output of enhanced CFP (ECFP) and EGFP, respectively. As a proof of concept, we modified reporter cells with CD19-specific and ROR1-specific CARs, and we detected high-level reporter signals that allowed distinguishing functional from non-functional CAR constructs. The reporter data were highly reproducible, and the time required for completing each testing campaign was substantially shorter with reporter cells (6 days) compared to primary CAR-T cells (21 days). We challenged the reporter platform to a large-scale screening campaign on a ROR1-CAR library, and we showed that reporter cells retrieved a functional CAR variant that was present with a frequency of only 6 in 1.05 × 106. The data illustrate the potential to implement this reporter platform into the preclinical development path of novel CAR-T cell products and to inform and accelerate the selection of lead CAR candidates for clinical translation.

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Chimeric antigen receptors enable superior control of HIV replication by rapidly killing infected cells.

Project description:Engineered T cells hold great promise to become part of an effective HIV cure strategy, but it is currently unclear how best to redirect T cells to target HIV. To gain insight, we generated engineered T cells using lentiviral vectors encoding one of three distinct HIV-specific T cell receptors (TCRs) or a previously optimized HIV-targeting chimeric antigen receptor (CAR) and compared their functional capabilities. All engineered T cells had robust, antigen-specific polyfunctional cytokine profiles when mixed with artificial antigen-presenting cells. However, only the CAR T cells could potently control HIV replication. TCR affinity enhancement did not augment HIV control but did allow TCR T cells to recognize common HIV escape variants. Interestingly, either altering Nef activity or adding additional target epitopes into the HIV genome bolstered TCR T cell anti-HIV activity, but CAR T cells remained superior in their ability to control HIV replication. To better understand why CAR T cells control HIV replication better than TCR T cells, we performed a time course to determine when HIV-specific T cells were first able to activate Caspase 3 in HIV-infected targets. We demonstrated that CAR T cells recognized and killed HIV-infected targets more rapidly than TCR T cells, which correlates with their ability to control HIV replication. These studies suggest that the speed of target recognition and killing is a key determinant of whether engineered T cell therapies will be effective against infectious diseases.

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