Daily Respiratory Research Analysis
Analyzed 211 papers and selected 3 impactful papers.
Summary
A phase 3 randomized trial in Nature Cancer found no progression-free or overall survival benefit from adding nivolumab±ipilimumab to chemoradiotherapy versus durvalumab consolidation in unresectable stage III NSCLC, with more pneumonitis, informing practice. Mechanistic work in Advanced Science identifies macrophage-to-myofibroblast transdifferentiation via a MERTK–SPP1–SRC–TKS5 axis as a driver of pulmonary fibrosis and a potential therapeutic target. A nationwide cohort (NORDSTAR) in AJRCCM delineates risk factors and high-risk profiles for progression from mild-to-moderate to severe asthma, supporting earlier risk stratification.
Research Themes
- Immunotherapy strategies after chemoradiotherapy in stage III NSCLC
- Macrophage-to-myofibroblast transdifferentiation driving pulmonary fibrosis
- Risk stratification for progression to severe asthma
Selected Articles
1. Nivolumab plus chemoradiotherapy followed by nivolumab with or without ipilimumab for untreated locally advanced stage III NSCLC: a randomized phase 3 trial.
In unresectable stage III NSCLC, adding nivolumab±ipilimumab to CCRT did not improve PFS or OS compared with standard durvalumab consolidation and increased pneumonitis. These negative findings argue against replacing durvalumab maintenance after CCRT and underscore the need for alternative strategies.
Impact: A large phase 3 RCT in a high-burden setting provides definitive evidence that nivolumab-based peri-CCRT regimens do not surpass durvalumab, immediately informing guideline-concordant care and avoiding excess toxicity.
Clinical Implications: Durvalumab remains the consolidation standard after CCRT for unresectable stage III NSCLC. Clinicians should avoid substituting nivolumab±ipilimumab in this setting and be vigilant for pneumonitis with ICIs plus CCRT.
Key Findings
- No PFS benefit for nivolumab+ipilimumab vs durvalumab (HR 0.95; 96% CI 0.77–1.19; P=0.65).
- No OS improvement for nivolumab+ipilimumab (HR 1.12; 95% CI 0.87–1.43) or nivolumab alone (HR 0.97; 95% CI 0.76–1.24) vs durvalumab.
- Higher pneumonitis incidence with nivolumab-based arms compared with durvalumab consolidation.
Methodological Strengths
- Phase 3 randomized design with three-arm comparison and predefined endpoints
- Adequate follow-up (median 30.5 months) and robust hazard ratio estimates
Limitations
- Pneumonitis signal limits generalizability of intensified regimens
- No biomarker-enriched subgroup analyses reported to identify potential beneficiaries
Future Directions: Explore alternate radiosensitizers, novel consolidation agents, and biomarker-driven strategies that minimize pneumonitis while improving survival after CCRT.
Over 50% of persons with unresectable stage III non-small cell lung cancer (NSCLC) treated with standard-of-care concurrent chemoradiotherapy (CCRT) and durvalumab consolidation progress or die within 18 months. Here adults with untreated, unresectable stage III NSCLC were randomized to nivolumab plus CCRT followed by consolidation with nivolumab plus ipilimumab (arm A) or nivolumab alone (arm B) or CCRT followed by consolidation with durvalumab (arm C). The primary endpoint was progression-free survival (PFS) in arm A versus arm C and secondary endpoints included overall survival (OS), PFS in arm B versus arm C, response rates and safety. At a median follow-up of 30.5 months, there was no statistically significant difference in the primary endpoint of PFS in the nivolumab plus ipilimumab arm versus durvalumab arm (hazard ratio (HR): 0.95, 96% confidence interval (CI): 0.77-1.19; P = 0.65). Descriptive OS analysis showed no improvement (HR: 1.12, 95% CI: 0.87-1.43). Nivolumab alone did not improve PFS or OS versus durvalumab (PFS, HR: 0.84, 95% CI: 0.69-1.04; OS, HR: 0.97, 95% CI: 0.76-1.24). Nivolumab plus ipilimumab and nivolumab alone plus CCRT resulted in increased pneumonitis. These results emphasize the need for novel efficacious treatments for these individuals. (ClinicalTrials.gov: NCT04026412 ).
2. Macrophage-to-Myofibroblast Transdifferentiation Contributes to Pulmonary Fibrosis via the MERTK-SPP1-SRC-TKS5 Signaling Axis.
This study demonstrates that macrophage-to-myofibroblast transdifferentiation operates in IPF and bleomycin models, driven by a GAS6–MERTK–SPP1–SRC–TKS5 axis. Genetic/viral disruption of MERTK or TKS5 suppresses MMT and attenuates fibrosis, nominating this signaling cascade as a therapeutic target.
Impact: Establishes a causal, targetable signaling pathway for MMT in pulmonary fibrosis with in vivo functional validation, advancing mechanistic understanding and therapeutic avenues.
Clinical Implications: While preclinical, the data support development of agents modulating MERTK–SPP1–SRC–TKS5 to suppress fibroblast accrual and matrix deposition in fibrosis.
Key Findings
- Confirmed MMT in human IPF lungs and bleomycin-induced mouse lungs using immunologic and molecular assays.
- Identified a GAS6–MERTK–SPP1–SRC–TKS5 cascade that drives MMT.
- Macrophage-specific MERTK knockout or AAV-mediated TKS5 knockdown suppressed MMT and reduced fibrosis by microCT, PFT, and histology.
Methodological Strengths
- Multi-system validation (human IPF tissue and murine model) with molecular perturbation
- Comprehensive outcome assessments including imaging, physiology, and histopathology
Limitations
- Preclinical models may not fully capture chronic human disease dynamics
- Safety and specificity of targeting this axis require pharmacologic validation
Future Directions: Develop selective small-molecule/biologic inhibitors of the axis; assess efficacy in diverse fibrosis models and human ex vivo systems; define biomarkers of MMT activity.
In recent years, macrophage-to-myofibroblast transdifferentiation (MMT) has been found in fibrosis-related diseases. We confirmed the presence of MMT in human idiopathic pulmonary fibrosis (IPF) lungs and bleomycin-induced murine model using immunological and molecular methods. Mechanistically, ligand (GAS6)-mediated activation of MERTK on macrophages initiates a sequential signaling cascade involving SPP1, SRC, and TKS5, which collectively drives the transdifferentiation program. Conversely, knockout of MERTK specifically in macrophages or adeno-associated virus (AAV)-mediated knockdown of TKS5 effectively disrupted this MERTK-SPP1-SRC-TKS5 axis, potently suppressing MMT in vitro and in vivo. These interventions significantly attenuated the progression of pulmonary fibrosis, as evidenced by comprehensive assessments including microCT, pulmonary function test, and histopathological analysis. Our findings establish MMT as a key pathogenic mechanism and identify the MERTK-initiated signaling axis as a novel therapeutic target.
3. From mild-to-moderate to severe asthma: Risk factors and patient profiles from the NORDSTAR cohort.
In a nationwide cohort of 99,748 adults after a first exacerbation, only 4.1% progressed to severe asthma over 5 years, but distinct profiles—age 40–49, medium-dose ICS at exacerbation, high SABA use, recurrent infections, and eosinophilia—had up to 30.4% 5-year risk. These data support early identification and targeted management of high-risk phenotypes.
Impact: The sheer scale and robust modeling delineate actionable risk profiles for progression to severe asthma, informing precision prevention strategies following a first exacerbation.
Clinical Implications: Clinicians can use these factors (eosinophilia, SABA overuse, infections, medium-dose ICS failure) to flag patients for intensified controller optimization, infection prevention, and closer follow-up to reduce progression risk.
Key Findings
- Among 99,748 adults after a first exacerbation, 4.1% progressed to severe asthma within 5 years.
- Independent risk factors: age 40–49 (OR 1.62), exacerbation on medium-dose ICS (OR 3.72), high SABA use (OR 1.76), ≥2 respiratory infections (OR 1.61), eosinophils ≥0.6×10^9/L (OR 1.97).
- A specific late-onset eosinophilic profile on medium-dose ICS with recurrent infections had 30.4% 5-year progression risk.
Methodological Strengths
- Very large, nationally representative cohort with 5-year follow-up
- Multivariable modeling to control confounding and define risk profiles
Limitations
- Observational design susceptible to residual confounding and misclassification
- Findings from Danish healthcare context may limit external generalizability
Future Directions: Prospective validation and interventional trials to test whether targeted intensification post-first exacerbation reduces transition to severe asthma.
BACKGROUND: The progression from mild-to-moderate to severe asthma remains unclear. This study aimed to assess the risk of progression following the first asthma exacerbation in mild-to-moderate asthma and to identify risk factors and high-risk patient profiles. METHODS: This was an observational cohort study based on Danish data from the NORdic Dataset for aSThmA Research (NORDSTAR) research collaboration platform. Adult patients with mild-to-moderate asthma experiencing their first asthma exacerbation were identified between 2000-2018 and followed prospectively for five years for the development of severe asthma according to ERS/ATS guidelines. Baseline risk factors for progression to severe asthma were assessed using multivariable logistic regression models and risk of progression was evaluated across specific patient profiles. RESULTS: Among 99,748 patients with mild-to-moderate asthma experiencing the first asthma exacerbation, 4.1% progressed to severe asthma within five years. Risk factors included baseline age 40-49 years [odds ratio (OR): 1.62 (95% CI: 1.49, 1.77), experiencing an exacerbation despite medium dose inhaled corticosteroid (ICS) use [OR: 3.72 (3.39, 4.09)], high use of short-acting beta agonist [OR: 1.76 (1.64, 1.90)], ≥2 respiratory infections [OR: 1.61 (1.49-1.73)], and blood eosinophil counts ≥ 0.6 × 109/L [OR: 1.97 (1.47-2.61)]. A 40-49-year-old patient with late-onset eosinophilic asthma, treated with medium-dose ICS and with recurrent respiratory infections, had a 30.4% five-year risk of progressing to severe asthma. CONCLUSION: In patients with mild-to-moderate asthma experiencing their first asthma exacerbation, few patients (4.1%) overall progressed to severe asthma within five years, but specific high-risk patient profiles faced risks of up to 30%. Whether early recognition can modify this risk warrants further investigation.