Identifying response defining mechanisms for biological therapies in severeasthma (insights ); assessing the role of CD4-ctls

The National Heart, Lung, and Blood Institute (NHLBI) awarded San Diego Biomedical Research Institute a Project Grant of $1,436,586 on September 20, 2025, under the Cardiovascular Diseases Research program (CFDA 93.837) to conduct the INSIGHTS study, which assesses the role of CD4+ cytotoxic T lymphocytes (CD4-CTLs) in severe asthma pathogenesis and response to Type 2 (T2) biologic therapies. The research aims to analyze airway CD4-CTLs from blood and sputum samples collected from 160 severe asthmatic patients across three clinical centers—University of Southampton (UK), University of Michigan (Ann Arbor), and University of California, San Diego (UCSD)—before and at 12 and 24 months following initiation of T2-biologic therapy. The study is led by a multidisciplinary team of clinical asthma and immuno-genomics experts and will evaluate the impact of CD4-CTLs on T2-biologics response through extensive clinical analysis.

Under this award, UCSD was designated as a sub-awardee (sub-award date February 24, 2026) to recruit patients with severe asthma, with targeted enrollment of 30 Hispanic patients leveraging UCSD's established cohort of well-characterized severe asthma patients from the PrecISE study. The project period extends through June 30, 2027, and deliverables include comprehensive single-cell transcriptome analysis, clinical assessments linking CD4-CTL proportions to asthma severity and lung function outcomes, and data supporting understanding of alternative pathophysiological drivers beyond T2 inflammation in severe asthma.

Abstract

Severe asthma, characterized by persistent airway inflammation and corticosteroid resistance, afflicts millions of americans with limited therapeutic options. Clinicians currently rely on type 2 immune biomarkers for patient classification (T2HIGH VS. T2LOW) and treatment decisions. However, real-world studies revealed the over- representation of the T2HIGH endotype in severe asthma and those treated with anti-T2 biologic therapies exhibit contrasting responses, challenging the efficacy of this T2 dichotomy and highlighting the need to explore alternative pathophysiological drivers. Our single-cell transcriptome analysis of t cells from inflamed airways in severe asthmatics identified a novel subset of pathogenic airway tissue resident cytotoxic CD4+ t cells (CD4-ctls). Despite biologic treatment, CD4- ctls remained activated, producing inflammatory molecules. Cell proportions analysis linked CD4-ctls to asthma severity and lung function impairment, particularly in males with late-onset asthma. The study strongly supports CD4-ctls' significant contribution to airway inflammation, potentially hindering T2-biologic response. Led by a multidisciplinary team of experts in clinical asthma, and immuno-genomics, DRS. Kurukulaaratchy and seumois, our insights study aims to assess the impact of CD4-ctls on severe asthma pathogenesis and T2- biologics response at a larger scale. Aim 1: we will analyze airway CD4-ctls from blood and sputum samples collected from 160 severe asthmatic patients before, and 12- and 24- months after initiating T2-biologic therapy. We will evaluate the impact of CD4- ctls on T2-biologics response through extensive clinical analysis. Samples will be collected by three clinical centers [university of southampton, UK; university of michigan, ANN arbor, US, and university of california, SAN diego, US] establishing the clinical significance of CD4-CTL as a new player in asthma pathogenesis. Aim 2: with the planned collection of samples, we will generate up to 1 million single-CD4-CTL cell transcriptomes allowing US to comprehensively decipher the pathogenic cellular and molecular features of CD4- ctls in asthma severity and response to T2-biologics, as well as investigate their function through TCR- reactivity and interactions with structural cells analysis. In summary, this unique translational proposal aims to unveil mechanisms causing a lack or loss of response to T2-biologics in severe asthma, focusing on CD4-ctls. Findings could establish CD4-ctls as a better predictor for patient stratification, leading to novel therapies for unmet patient needs.