In a groundbreaking development poised to redefine the treatment landscape for mesothelioma, researchers have unveiled promising results from an early-phase clinical trial that integrates combination immunotherapy with surgical intervention. Presented at the prestigious World Conference on Lung Cancer in Barcelona, Spain, and concurrently published in the esteemed journal Nature Medicine on September 8th, 2025, this study marks a pivotal moment in mesothelioma research—a rare but aggressive cancer known to affect the pleural lining of the lungs and commonly linked to asbestos exposure.
Led by Professor Patrick Forde of the Trinity St. James’s Cancer Institute (TSJCI) and the School of Medicine at Trinity College Dublin, this clinical trial represents the first investigation into the perioperative use of dual immune checkpoint inhibitors nivolumab and ipilimumab in patients with resectable diffuse pleural mesothelioma. Globally, mesothelioma affects approximately 30,000 individuals annually, with about 50 cases diagnosed each year in Ireland, highlighting the critical need for innovative therapeutic strategies beyond conventional surgery and chemotherapy.
The clinical conundrum with mesothelioma has long been the tumor’s infiltrative nature; it aggressively spreads along the pleural surfaces, making complete surgical resection exceedingly challenging, and thus limiting surgical cure rates. Immunotherapy, specifically agents targeting immune checkpoints PD-1 and CTLA-4, has revolutionized oncological treatments by enhancing the patient’s immune system to recognize and attack cancer cells, offering hope in advanced-stage mesothelioma. Nevertheless, until now, the utility of these agents in the neoadjuvant (pre-surgical) setting had remained unexplored.
Prof. Forde, a leading figure in immuno-oncology with a robust portfolio of lung cancer clinical trials, emphasized the innovative premise underlying this study: harnessing the immune system prior to surgical intervention could potentially improve not only the feasibility of surgery but also enhance long-term survival outcomes. By initiating checkpoint inhibitor treatment six weeks before surgery and continuing immunotherapy for up to one year postoperatively, the study tested the hypothesis that the immune system could be primed to eradicate microscopic residual disease and reduce recurrence rates.
The trial design involved randomizing patients to receive either monotherapy with nivolumab or combination immunotherapy with nivolumab plus ipilimumab. Remarkably, patients tolerated the treatment well, with low incidences of serious adverse events, and crucially, all were able to proceed safely to surgery. The safety profile observed here is particularly consequential, as concerns about potential immunotherapy-induced perioperative complications have historically impeded neoadjuvant exploration in mesothelioma.
Follow-up analyses revealed that those receiving combination immunotherapy exhibited survival benefits exceeding historical controls from prior mesothelioma trials devoid of immunotherapeutic intervention. While these results are preliminary given the early phase and limited patient numbers, they portend a meaningful clinical impact and set the stage for subsequent larger scale, randomized trials that could validate and potentially establish new therapeutic standards.
In a significant scientific collaboration with Johns Hopkins University, the research team also delved into the emerging field of circulating tumor DNA (ctDNA) surveillance. By sequencing ctDNA from patients’ blood samples drawn before and during treatment, investigators sought to identify molecular biomarkers predictive of therapeutic response. Their findings suggest that dynamic monitoring of tumor-derived genetic fragments in circulation not only forecasts the likelihood of successful surgical outcomes but also signals the potential risk of relapse. This represents a paradigm shift toward personalized treatment algorithms wherein real-time molecular monitoring complements clinical decision-making.
Professor Forde expressed cautious optimism about these findings, underscoring the translational significance of combining immunotherapy with surgery and molecular diagnostics. “Our research illuminates a new frontier in early mesothelioma treatment, leveraging the patient’s immune system at the earliest possible juncture to augment tumor eradication and improve survival,” he stated. “TSJCI continues to spearhead cutting-edge clinical trials, aiming to broaden patient access to innovative therapies and translate basic immunologic insights into tangible clinical benefits.”
This research also highlights the strategic importance of Ireland’s Trinity St. James’s Cancer Institute, the nation’s first internationally accredited Comprehensive Cancer Centre, which since 2024 has been under Prof. Forde’s leadership as Prendergast Professor of Immuno-Oncology. The institute’s mission to intertwine advanced clinical research with community-based care infrastructure has enabled rapid deployment and evaluation of novel interventions in diverse cancer populations across Ireland and Europe.
Mesothelioma poses unique challenges including limited early detection tools, intrinsic resistance to standard therapies, and a historically grim prognosis. The emergence of immunotherapy has begun to challenge these entrenched obstacles, with the combined modality approach underscored by this trial representing a critical evolution. By administering checkpoint inhibitors in the perioperative window, the immune system is activated to detect and eliminate tumor cells not only at the primary site but also potentially at distant micrometastatic niches.
Moreover, the integration of ctDNA analyses introduces an exciting dimension of precision oncology, enabling clinicians to tailor treatment intensity and duration based on molecular responses rather than purely radiographic or clinical parameters. This could substantially reduce overtreatment risks while maximizing efficacy, fostering a shift toward adaptive immunotherapy paradigms.
The phase 2 trial’s insights extend beyond mesothelioma, offering a conceptual framework that might be extrapolated to other thoracic malignancies and solid tumors treated surgically. The notion of “immune priming” before cytoreductive interventions is gaining momentum, supported by accumulating evidence that neoadjuvant immunotherapy can reshape the tumor microenvironment to facilitate immune cell infiltration, improve antigen presentation, and perhaps induce long-lasting systemic anti-tumor immunity.
Nonetheless, challenges remain. Larger confirmatory studies will be essential to establish statistical significance, optimize dosage and timing regimens, and define patient subgroups most likely to benefit. Long-term monitoring is also needed to assess durability of response and potential late toxicities inherent to immune checkpoint blockade. Furthermore, the mechanistic underpinnings of immunotherapy synergy with surgery require deeper exploration, including the role of tumor mutational burden, immune cell repertoire changes, and stromal remodeling.
As research efforts progress, interdisciplinary collaboration between oncologists, immunologists, thoracic surgeons, and molecular biologists will be crucial to unlock the full potential of combination treatments. Equally, expanding patient access to such trials through centralized cancer centers and international cooperation remains a global priority.
In sum, this seminal trial offers a beacon of hope for mesothelioma patients who previously faced limited therapeutic options and poor survival odds. By strategically integrating immune checkpoint inhibitors in the preoperative setting and leveraging cutting-edge molecular diagnostics, the study pioneers a novel approach that could transform clinical practice. The oncology community eagerly anticipates subsequent data releases and hopes this innovative paradigm will serve as a catalyst for accelerating the integration of immunotherapy across surgical oncology.
Subject of Research: People
Article Title: Perioperative nivolumab or nivolumab plus ipilimumab in resectable diffuse pleural mesothelioma: a phase 2 trial and ctDNA analyses
News Publication Date: 8-Sep-2025
