🎯 Background & Rationale
Pleural mesothelioma (PM) is a rare, aggressive malignancy historically driven by asbestos exposure with a characteristically poor prognosis and an immunosuppressive tumor microenvironment. While frontline chemoimmunotherapy combinations (such as nivolumab plus ipilimumab) and chemoimmunotherapy regimens have improved overall survival compared to historical chemotherapy standards, median overall survival remains low (approximately 18 months), and durable curative options are absent. Predictive biomarkers for immunotherapy remain unvalidated in routine clinical practice. Furthermore, translating novel targeted and immunotherapeutic strategies is severely hampered by the limitations of conventional mouse models, which fail to capture human interpatient heterogeneity and cannot properly test therapies directed against human-specific targets. This review addresses both the evolving clinical landscape of PM immunotherapy and the critical need for advanced human preclinical models (such as spheroids, organoids, patient-derived xenografts, and organ-on-chip platforms) to study drug resistance and optimize therapeutic strategies.
👥 Study Design & Population
- Type of Publication: State-of-the-Art Review / Comprehensive Narrative Literature Review.
- Population: Adult patients with unresectable malignant pleural mesothelioma (epithelioid, biphasic, and sarcomatoid histologies), evaluated across multiple referenced phase I, II, and III clinical trials (e.g., CheckMate 743, MAPS, MAPS-2, CONFIRM, PROMISE-meso, IND227/KN483, ETOP BEAT-meso) as well as real-world cohorts.
- Interventions / Focus: Review of clinical data regarding immune checkpoint inhibitors (ICIs) alone or combined with chemotherapy, anti-angiogenics, and alternative immunotherapies (gene therapy, intrapleural photodynamic therapy, CAR T-cell therapy, dendritic cell vaccines, oncolytic viruses, and antibody-drug conjugates), alongside a comprehensive critique of human preclinical models (cell lines, spheroids, organoids, patient-derived organotypic tumour spheroids [PDOTs], patient-derived xenografts [PDXs], and humanized murine models).
📈 Methodology & Rigor
The authors performed an extensive literature review utilizing personal expertise and PubMed searches focusing on keywords including “(pleural) mesothelioma, immunotherapy, preclinical models, and cell models.” The review rigorously synthesizes findings from major randomized controlled trials, phase I–III clinical studies, and recent single-cell RNA sequencing (scRNASeq) translational investigations. Methodological rigor is demonstrated by critically analyzing the discrepancies between clinical trial outcomes (e.g., CheckMate 743 vs. PROMISE-meso) and evaluating the physiological relevance, advantages, and limitations of various human versus murine experimental models.
🔬 Key Findings [or Planned Endpoints]
- Clinical Landscape & Survival: First-line dual immunotherapy (nivolumab + ipilimumab) demonstrated a significant overall survival benefit over chemotherapy in CheckMate 743 (mOS 18.1 vs 14.1 months), with particularly pronounced efficacy in non-epithelioid histologies. Chemotherapy combined with pembrolizumab (IND227/KN483) also showed an improved mOS of 17.3 months versus 16.1 months with chemotherapy alone.
- Biomarkers & Microenvironment: Tumor PD-L1 expression remains unvalidated as a routine standalone predictive biomarker. Recent scRNASeq data reveal deep tumor microenvironment heterogeneity, linking high sarcomatoid transcriptional phenotypes (high S-Score) to CD8 effector/exhausted T-cell and regulatory T-cell enrichment, and identifying novel targets such as NK cell inhibitory interactions (NKG2A/HLA-E) and macrophage-driven immunosuppression (TAMs).
- Alternative Preclinical Models: Classical 2D cell lines and homogenous mouse models fail to capture interpatient heterogeneity and human-specific immunologic targets. The review highlights the advantages of 3D human spheroids (incorporating spatial gradients, hypoxia, and modular immune cell co-cultures like TAMs or neutrophils), organoids, patient-derived organotypic tumor spheroids (PDOTs), and humanized PDX models in faithfully replicating patient tumor biology, testing drug penetration, and evaluating novel immunotherapeutic and targeted agents.
⚖️ Critical Appraisal
As a comprehensive state-of-the-art review, the paper provides a balanced synthesis of practice-changing clinical data and translational modeling limitations. While narrative reviews inherently lack the quantitative pooling of a meta-analysis, the authors transparently acknowledge the limitations of current clinical trials (such as premature trial closures due to slow accrual in DREAM3R or conflicting results in chemoimmunotherapy trials) and detail the specific weaknesses of preclinical models—notably the lack of a fully functional immune system in standard organoids/spheroids, the loss of human microenvironments over passages in PDXs, and high financial and technical costs associated with humanized murine models.
💡 The Clinical Bottom Line
For the clinician and interventionalist, immunotherapy (such as nivolumab plus ipilimumab or pembrolizumab-chemotherapy combinations) has reshaped the standard of care for unresectable pleural mesothelioma, particularly benefiting non-epithelioid subtypes. However, significant toxicity and resistance remain major hurdles. In the bronchoscopy and procedural suite, this review underscores the vital importance of acquiring high-quality fresh tissue and pleural fluid samples during diagnostic procedures (such as medical thoracoscopy/VATS) to feed emerging translational pipelines—including organoid, spheroid, and single-cell platforms—which are essential for developing personalized, biomarker-driven therapies and overcoming resistance in this challenging malignancy.