bims-mesote 2026-06-21 papers

Issue of 2026–06–21
five papers selected by
Laura Mannarino, Humanitas Research

Front Oncol. 2026 ;16 1841585

Trop-2 expression is associated with poor survival in pleural mesothelioma.

Alejandro Aviles-Salas, Norma Hernández-Pedro, Enrique Caballé-Perez, José Lucio-Lozada, César Castillo-Ruiz, José Gregorio Chanona-Vilchis, Alejandro Aranda-Gutierrez, Mario Orozco-Morales, Pedro Barrios-Bernal, Rafael Parra-Medina, Luis Cabrera-Miranda, Andrés F Cardona, Oscar Arrieta.

Introduction: Pleural mesothelioma (PM) lacks reliable biomarkers to guide therapy. Trophoblast cell-surface antigen 2 (Trop-2) is targetable in epithelial cancers, but its prevalence and clinical relevance in PM remain unclear.
Methods: This retrospective cohort study selected patients with PM at the Instituto Nacional de Cancerología of Mexico from 2010 to 2022. Two independent pathologists evaluated Trop-2 positivity in histological tumor samples, defined as specific membranous staining of any intensity in ≥1% of analyzed tumor cells, equivalent to an H-score ranging 1 to 300. Median progression-free survival (mPFS) and overall survival (mOS) stratified by Trop-2 status were estimated by Kaplan-Meier method, and clinicopathologic associations were adjusted by multivariable Cox models.
Results: Among sixty cases, Trop-2 was positive in 12 cases, associated with lung (p = 0.016) and non-regional lymph nodes (p = 0.002) metastases, shorter mOS (7.9 vs 27.8 months; p = 0.021), and independently predicted of worse PFS (adjusted hazard ratio [aHR] 2.20; p = 0.048) and OS (aHR 3.79; p = 0.009). Poorer OS was also predicted by Sarcomatoid histology (aHR 6.19; p = 0.025) and PLECH score >3 (aHR 2.64; p = 0.025).
Discussion: Despite this small sample size, Trop-2 was related to adverse clinical outcomes, which may represent a key vulnerability for antibody-drug conjugates in PM, and highlight the need for its prospective standardized evaluation.
Conclusions: Trop-2 was expressed in 20% of PMs, exclusively in epithelioid histology, associated with advanced disease and poor survival outcomes. These results support the prospective evaluation of Trop-2-targeted therapies in PM.

Keywords: chemotherapy; pleural mesothelioma; prognostic biomarkers; survival; trophoblast cell-surface antigen 2

DOI: https://doi.org/10.3389/fonc.2026.1841585

Clin Lung Cancer. 2026 May 27. pii: S1525-7304(26)00072-0. [Epub ahead of print]27(6): 31-35

CHIMERA: A Phase II Study of Neoadjuvant Pembrolizumab in Combination With Cisplatin or Carboplatin and Pemetrexed Followed by Surgery and Adjuvant Pembrolizumab in Resectable Pleural Mesothelioma.

Giulia Pasello, Daniela Scattolin, Eleonora Faccioli, Paolo Andrea Zucali, Giuseppe Marulli, Federica Grosso, Giovanni Luca Ceresoli, Marcello Tiseo, Alessandra Bearz, Fabiana Letizia Cecere, Luana Calabrò, Francesco Callegarin, Paola Del Bianco, Gian Luca De Salvo, Federica Pezzuto, Fiorella Calabrese, Valentina Guarneri, Andrea Dell'Amore, Federico Rea.

Pleural mesothelioma (PM) is a rare asbestos-related malignancy characterized by complex diagnosis and poor prognosis, with survival strongly influenced by histological subtype and eligibility for a multimodality approach, reserved for highly selected patients. While platinum-pemetrexed chemotherapy or the combination of ipilimumab plus nivolumab represent standard first-line options for unresectable disease, pembrolizumab combined with platinum-pemetrexed has demonstrated improved survival in advanced PM (IND227/Keynote483 trial). In resectable PM, multimodality treatment including surgery and chemotherapy remains preferred, yet pathological complete response (pCR) rates remain low at approximately 5%, and the role of perioperative immunotherapy is still poorly defined. CHIMERA is a prospective, open-label, multicenter phase II single-arm trial evaluating neoadjuvant pembrolizumab combined with platinum-pemetrexed chemotherapy followed by surgery and adjuvant pembrolizumab in patients with treatment-naïve, resectable stage I-IIIA epithelioid or biphasic PM. Patients receive three cycles of neoadjuvant pembrolizumab plus cisplatin or carboplatin and pemetrexed every three weeks, followed by centralized pleurectomy/decortication or extended pleurectomy/decortication in two high-volume referral centers, and subsequently 14 cycles of adjuvant pembrolizumab. The primary endpoint is pCR, with secondary endpoints including major pathological response, objective response rate, event-free survival, overall survival, treatment feasibility, and safety; translational tissue- and blood-based biomarker analyses are planned. The study is powered to detect an increase in pCR from 5% to 18%, requiring 40 patients to account for potential dropouts. By focusing on pathological efficacy within a standardized multimodality framework, CHIMERA aims to clarify the role of perioperative chemo-immunotherapy and to improve outcomes for patients with resectable PM.

Keywords: Immunotherapy; Multimodality; Perioperative; Pleural Mesothelioma; Pleurectomy

DOI: https://doi.org/10.1016/j.cllc.2026.05.004

J Thorac Dis. 2026 May 31. 18(5): 516

Pressurized intrathoracic aerosol chemotherapy (PITAC) for malignant pleural mesothelioma-ex vivo evaluation of optimal treatment conditions and comparison with hyperthermic intrathoracic chemotherapy (HITOC).

Katharina Flöthmann, Norman Zinne, Peter Braubach, Alina Meininger, Imke Becker, Nicole Ernst, Arjang Ruhparwar, Hayan Merhej, Patrick Zardo.

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive disease with poor prognosis and limited treatment options. Pressurized intrathoracic aerosol chemotherapy (PITAC) has emerged as a novel approach for intrathoracic drug delivery. The aim of this study was to investigate cisplatin penetration characteristics and to evaluate procedural parameters influencing drug penetration, including temperature, drug concentration and pleural barrier function, in an ex vivo model. In addition, PITAC was compared with hyperthermic intrathoracic chemotherapy (HITOC), a treatment modality applied in selected specialized centers as part of multimodal treatment concepts for MPM.
Methods: We investigated the penetration depth and intensity of aerosolized cisplatin generated using a high-pressure nebulizer in an ex vivo setting. Potential influencing factors, including temperature, cisplatin concentration and barrier function of the pleura, were gradually modified, as we sought to evaluate optimal procedural conditions. Finally, PITAC was compared with a previously standardized HITOC approach.
Results: A temperature of 42 ℃, a cisplatin concentration of 1 mg/mL, and prior removal of the pleura, improved the penetration depth and intensity of the chemotherapeutic agent. Under clinically relevant experimental conditions, aerosolized cisplatin application demonstrated greater tissue penetration compared to HITOC.
Conclusions: Our preclinical data suggest that PITAC may be a viable alternative to HITOC and warrants further clinical investigation.

Keywords: Pressurized intraperitoneal aerosol chemotherapy (PIPAC); hyperthermic intrathoracic chemotherapy (HITOC); mesothelioma; pressurized intrathoracic aerosol chemotherapy

DOI: https://doi.org/10.21037/jtd-2026-1-0258

Lancet Oncol. 2026 Jun 17. pii: S1470-2045(26)00084-7. [Epub ahead of print]

Development and validation of artificial intelligence-assisted volumetric response criteria in pleural mesothelioma (ARTIMES): a retrospective, multicohort, multicentre study.

BACKGROUND: Response evaluation in pleural mesothelioma is challenging because its crescent growth pattern is poorly captured by diameter-based criteria. We aimed to develop and validate artificial intelligence (AI)-assisted volumetric response criteria (ARTIMES) based on automated tumour segmentation and biologically derived thresholds.
METHODS: In this retrospective, multicentre study, we included 10 926 CT scans from 2080 patients from 14 cohorts. A subset totalling 1176 CT scans from routine care (Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital) and trial cohorts (INITIATE, NivoMes, PEMMELA, LUME-MESO, NVALT19, and MiST1 trials) was annotated by 12 radiologists and 1 pulmonologist, supplemented by 100 negative CT scans, to train a deep-learning segmentation model. Internal testing included 98 CT scans from independent international hospitals in LUME-MESO. External testing included data from the MEDUSA cohort (101 CT scans with radiologist-corrected segmentations) and two fully independent manual segmentation datasets from SAKK17/18 (22 CT scans) and the University of Chicago (15 CT scans). AI segmentations were evaluated through dice similarity coefficient (DSC) and normalised surface distance (NSD) at 3 mm. Progressive disease thresholds were derived using data from patients with multiple CT scans before first-line therapy or receiving only supportive care after first-line treatment (611 CT scans), and partial response thresholds from inter-reader variability (derived from 451 CT scans). ARTIMES was validated using data from eight clinical trials (4674 CT scans; 943 patients) and compared with modified Response Evaluation Criteria in Solid Tumors (mRECIST) using time-varying Cox proportional hazards models and trial-level surrogate endpoint analysis against overall survival using R2 and surrogate threshold effect.
FINDINGS: DSC was 94-95% in internal testing and 71-80% with manual segmentations. NSD was 98% and 81-93%, respectively. ARTIMES demonstrated superior patient-level prognostic performance compared with mRECIST (concordance index 0·83 [95% CI 0·79-0·87] vs 0·73 [0·66-0·80]; p=0·023) and detected progression a median of 5 weeks earlier (124 days [95% CI 115-126] vs 162 days [138-167]; p<0·0001). At the trial level, ARTIMES-based progression-free survival showed stronger correlation with overall survival (R2 88% [95% CI 42-100]) than did mRECIST-based progression-free survival (R2 6% [0-97]) and demonstrated a surrogate threshold effect at a progression-free survival hazard ratio of less than 0·82; no threshold was observed for mRECIST. Baseline AI-derived tumour volume independently predicted overall survival and outperformed T stage and WHO performance status.
INTERPRETATION: ARTIMES-based progression-free survival improves prognostic stratification and shows better trial-level surrogacy for overall survival compared with mRECIST-based progression-free survival. Pending prospective validation, ARTIMES could potentially facilitate a more reliable response evaluation in pleural mesothelioma.
FUNDING: Asbestos-Related Disease Section (SAGA) of the Dutch Society of Pulmonology and Tuberculosis (NVALT), Dutch Cancer Society, and Dutch Ministry of Health, Welfare and Sport.

DOI: https://doi.org/10.1016/S1470-2045(26)00084-7

Research (Wash D C). 2026 ;9 1310

Rejuvenated Hematopoietic Stem and Progenitor Cell-Engineered CAR-Armored Natural Killer T Cells for Malignant Pleural Mesothelioma.

Yan-Ruide Li, Yichen Zhu, Zhe Li, Xinyuan Shen, Shuo Li, Yuning Chen, Zibai Lyu, Jie Huang, Nathan Y Ma, Catherine Zhang, Annabel S Zhao, Yanxin Tian, Xianghong Jasmine Zhou, Lili Yang.

Malignant pleural mesothelioma (MPM) is a rare and highly aggressive malignancy arising from the pleural lining, characterized by a dismal prognosis and limited therapeutic options. Mesothelin (MSLN)-directed chimeric antigen receptor (CAR)-armored T (CAR-T) cell therapies have shown encouraging preliminary outcomes; however, autologous manufacturing approaches remain constrained by logistical complexity and prolonged production timelines, which are suboptimal for patients with rapidly advancing disease. Here, we describe the development of human allogeneic interleukin-15-augmented, MSLN-specific, CAR-armored invariant natural killer T (Allo15MCAR-NKT) cells. These cells are generated through genetic modification of hematopoietic stem and progenitor cells, followed by a clinically guided CAR-NKT cell differentiation, maturation, and expansion process. This approach supports scalable production with high cellular yield, purity, and translational feasibility. Functionally, Allo15MCAR-NKT cells exhibit robust antitumor efficacy in vitro and demonstrate robust therapeutic activity across multiple in vivo MPM xenograft models, including subcutaneous and lung metastasis models. In addition, they actively modulate the tumor microenvironment by targeting CD1d+ tumor-associated macrophages. Phenotypic analysis reveals a rejuvenated cellular profile, marked by low expression of exhaustion-associated and inhibitory receptors, including PD-1, TIM-3, LAG-3, CTLA-4, and TIGIT, consistent with sustained functional capacity. Importantly, these cells display a favorable safety profile, with minimal evidence of graft-versus-host disease, cytokine release syndrome, brain infiltration or neurotoxicity, and no detectable off-tumor effects. Collectively, these findings support the development of a clinically translatable, off-the-shelf CAR-NKT cell therapy for the treatment of MPM.

DOI: https://doi.org/10.34133/research.1310