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

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

PROVIDER: PRJNA1091584 | ENA |

REPOSITORIES: ENA

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	SRR28439030_1.fastq.gz	Fastqsanger.gz
	SRR28439030_2.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.

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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 [RNA-Seq]

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

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Longitudinal single-cell immunoprofiling links durable CAR T response to sustained activation and clonotypic expansion of the native cytotoxic T cell repertoire

Project description:CD19-directed chimeric antigen receptor (CAR) T-cell therapy has transformed outcomes for patients with relapsed/refractory large B-cell lymphoma (LBCL), yet the mechanisms underlying durable remission remain incompletely understood. While CAR T-cell persistence is associated with response, long-term remission can occur despite rapid CAR T clearance, suggesting the involvement of additional immune mechanisms. To investigate the role of the native T-cell repertoire in shaping response durability, we performed single-cell RNA and TCR sequencing (scRNA-seq/scTCR-seq) on longitudinal peripheral blood samples from LBCL patients treated with axicabtagene ciloleucel (axi-cel) in the ZUMA-1 trial. We compared immune landscapes and clonotypic dynamics among patients achieving durable remission (>1 year), those experiencing early relapse (<6 months), and those with refractory disease. Patients with long-term remission exhibited increased cytotoxic, proinflammatory, and proliferative native T-cell subsets, while early relapse was associated with immunoregulatory populations that may suppress T-cell activation. TCR profiling revealed robust clonotypic expansion of native cytotoxic T cells post-infusion in durable responders, with expansion patterns strongly predicting clinical outcomes. Notably, TCR screens did not identify known viral targets, suggesting tumor-specific immunity may mediate ongoing remission. These findings propose native T-cell clonotypic expansion as a key determinant of durable response to CAR T therapy and highlight its predictive potential for long-term clinical outcomes.

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