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A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [RNA-Seq]

ABSTRACT: A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [RNA-Seq]

PROVIDER: PRJNA1091579 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28438961.fastq.gz	Fastqsanger.gz
	SRR28438962.fastq.gz	Fastqsanger.gz
	SRR28438963.fastq.gz	Fastqsanger.gz
	SRR28438964.fastq.gz	Fastqsanger.gz
	SRR28438965.fastq.gz	Fastqsanger.gz

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A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [scRNA-Seq]

Project description:The majority of common chronic human diseases remain incurable, impacting a significant portion of the population and necessitating lifelong treatments that impose a substantial burden on health, the economy, and society. Asthma, the most prevalent respiratory disease, exemplifies this challenge, affecting over 300 million people and causing more than 250,000 deaths annually. Here, we demonstrate the achievement of long-term remission of type 2-high asthma through a single infusion of engineered CAR T cells. By utilizing IL-5 as the targeting domain and depleting BCOR and ZC3H12A, we engineer long-lived CAR T cells designed to eradicate IL-5R+ eosinophils, termed Immortal-like and Functional IL-5 CAR T (5TIF) cells. Furthermore, we enhance 5TIF cells by engineering them to secrete an IL-4 mutein that blocks the signaling of both IL-4 and IL-13, two inflammatory cytokines driving asthma pathology, resulting in the creation of 5TIF4 cells. In multiple asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, leads to long-term depletion of pathological eosinophils and blockade of IL-4/IL-13 actions. This results in sustained repression of type 2 inflammation and alleviation of asthmatic symptoms. Additionally, 5TIF4 cells can be induced in human T cells in NSG mice. These findings demonstrate that asthma, a prevalent and incurable disease, can undergo durable remission through a single infusion of engineered CAR T cells. This breakthrough paves the way for the potential functional cure of chronic noncancerous diseases using long-lived CAR T cells.

2024-04-04 | GSE262360 | GEO

A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [RNA-Seq]

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A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [scRNA-Seq]

Project description:A single infusion of engineered long-lived and multifunctional T cells confers durable remission of asthma in mice [scRNA-Seq]

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Multifactoral Immune Modulation Potentiates Durable Remission in Multiple Models of Aggressive Malignancy

Project description:Multifactoral Immune Modulation Potentiates Durable Remission in Multiple Models of Aggressive Malignancy

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Single-cell sequencing of infusion products and T cells after administration of non-viral PD1-targeted anti-CD19 CAR T cells

Project description:We successfully developed a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. In the adoptive therapy for relapsed/refractory aggressive B-cell non-Hodgkin lymphoma, we observed durable responses without serious adverse events and complete remission in patients treated with PD1 knockin CAR T cells. Here we applied single-cell sequencing to analyze the characteristcis of infusion products and T cells after administration.

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Single-cell CAR T atlas reveals type 2 function in 8-year leukaemia remission

Project description:Despite a high response rate in chimeric antigen receptor (CAR) T therapy for acute lymphocytic leukemia (ALL), approximately 50% of patients relapse within the first year, representing an urgent question to address in the next stage of cellular immunotherapy. To investigate the molecular determinants of ultra-long CAR T persistence, we obtained single-cell multi-omics sequencing data from 695,819 pre-infusion CAR T cells at the basal level or upon CAR-specific stimulation from 82 pediatric ALL patients enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type-2 functionality in CAR T infusion products was significantly associated with patients maintaining a median B-cell aplasia duration of 8.4 years. Analysis of ligand-receptor interactions unveiled that type-2 cells regulate a distinct dysfunctional population, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing functional fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of post-infusion sera revealed a higher level of circulating type-2 cytokines in 5-year or 8-year relapse-free responders. In a leukemic mouse model, type-2 high CAR T products demonstrated superior expansion and antitumor activity particularly upon leukemia rechallenge. Restoring antitumor efficacy in type-2 low CAR T cells was attainable by enhancing their type-2 functionality, either through incorporating IL-4 into the manufacturing process or priming manufactured CAR T products with IL-4 prior to infusion. Our findings provide key insights into the mediators of CAR T longevity and suggest potential therapeutic strategies to sustain long-term remission by boosting type-2 functionality in CAR T cells.

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