RARE DISEASE
Diffused pleural mesothelioma
Diffused pleural mesothelioma
Diffused pleural mesothelioma
Drug discovery
0
drugs
With orphan designations
Overview
Diffuse Pleural Mesothelioma (DPM) is an aggressive, asbestos-linked malignancy arising from mesothelial cells, predominantly affecting the pleura. Histologic subtypes include epithelioid (most common), biphasic, and sarcomatoid variants, with survival ranging from 4–27 months [1][17]. Diagnosis relies on imaging (CT/MRI), pleural fluid analysis, and biopsy with immunohistochemistry (BAP1/CDKN2A) [1][11]. Current therapeutic approaches prioritize multimodal strategies, including immunotherapy combinations, lung-sparing surgeries, and platinum-pemetrexed chemotherapy [5][13][17]. Prognosis remains poor, with median survival of 9–12 months [14][17].
Burden
Annual U.S. incidence: ~3,000 cases; 5-year survival rates: 12% (pleural) vs. 65% (peritoneal) [4][12].
High morbidity from pleural effusions, pain, and dyspnea; treatment costs exceed $60,000/year [4][11][17].
Global mortality remains stable, reflecting persistent asbestos exposure in developing nations [14][19].
Therapies
First-line: Dual immunotherapy (ipilimumab/nivolumab) for unresectable cases; platinum-pemetrexed ± bevacizumab [5][13][17].
Surgical: Lung-sparing pleurectomy/decortication preferred over pneumonectomy per 2025 ASCO guidelines [5][17].
Emerging: Targeted therapies (anti-mesothelin, PARP inhibitors) and tumor-treating fields under clinical evaluation [3][13][18].
Categories: rare neoplastic diseases, rare respiratory diseases
Research Papers
705 drug discovery papers about Diffused pleural mesothelioma, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
705 drug discovery papers about Diffused pleural mesothelioma, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-09-24 | Cytotoxic Microspinosamides from the Marine Sponge Geodia microspinosa That Decrease Diffuse Pleural Mesothelioma Viability.
A fraction from an extract of the marine sponge Geodia microspinosa was identified as active in a high-throughput screen for molecules that impair the viability of diffuse pleural mesothelioma (DPM) cell lines. Bioassay-guided isolation led to the identification of microspinosamides B and D, and a new artifact, microspinosamide C, together with two previously reported analogues, microspinosamide and polydiscamide B, as the active principles. Their planar structures were solved by NMR and HRESIMS analyses, while advanced Marfey's reaction, ROESY, and ECD were used for the establishment of their absolute configurations. All pure metabolites demonstrated low micromolar potency for the reduction in viability of the DPM cell lines.
2026-08-24 | [Ileal Perforation Caused by Pleural Mesothelioma-related Small Intestinal Involvement: A Case Report and Literature Review].
Pleural mesothelioma (PM) usually manifests as local intrathoracic invasion, and small intestinal involvement is rare. A 37-year-old man with initially diagnosed stage IV diffuse PM and no definite history of asbestos exposure or other specific occupational or environmental exposure except for long-term smoking was reported. After first-line treatment with Pemetrexed, Carboplatin and Bevacizumab, the disease remained stable. However, acute abdomen occurred during maintenance therapy, and emergency surgery confirmed terminal ileal perforation. Postoperative pathology suggested PM-related ileal involvement/metastatic involvement, with a higher Ki-67 proliferation index than that of the primary lesion. Because only perforation repair rather than segmental bowel resection was performed, the available pathological material could not determine whether full-thickness bowel-wall involvement was present or the direction of tumor invasion. Imaging findings, intraoperative findings and pathological results did not support primary peritoneal mesothelioma or direct contiguous invasion of the ileum by the diaphragmatic lesion; however, microscopic peritoneal dissemination with secondary bowel-wall involvement could not be completely excluded. The aim of this report, together with literature review, is to summarize the diagnostic challenges, management strategies and clinical implications of PM-related small intestinal involvement. .
2026-05-29 | Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity.
Investigating the biological mechanisms of acquired resistance to immunotherapy remains a necessity for effective treatment of solid tumors. Diffuse pleural mesothelioma (DPM) tumors, from immunocompetent and immunodeficient mouse models with acquired resistance to chimeric antigen receptor (CAR) T cell therapy were analyzed using flow cytometry, immunofluorescence, and ELISA. The interplay between genetic alterations in the cancer cell and site-specific tumor immune microenvironment (TIME) was characterized; therapies to reverse immunotherapy resistance were investigated. Analysis of tumors with acquired resistance to CAR T cell therapy demonstrated lower expression of tumor suppressor NF2. Enforced depletion of NF2 promoted resistance to CAR T cell and anti-PD-1 therapy in DPM but not in heterotopic subcutaneous tumors. Loss of NF2 was associated with accumulation of immunosuppressive complement receptor of immunoglobulin superfamily (CRIg)+ macrophages in pleural tumors, which was dependent on tumor-secreted chemokines and retinoic acid. Ablation of chemokines or pharmacologic inhibition of retinoic acid or the Hippo pathway by use of TEAD inhibitors restored sensitivity to CAR T cell therapy. Correspondingly, in two independent cohorts of patients, DPM tumors with NF2 copy-number loss, but not mutations, were associated with higher infiltration of M2 macrophages, lower infiltration and function of CD8 T cells, and an anti-PD-1-resistant gene signature. Our study uncovers a previously unknown mechanism of resistance to immunotherapy by identifying the dynamic interplay between cancer cell genetic alterations and the TIME. This research was funded in part through the NCI UG3CA290241, R01CA292664, R01CA235667, R01CA236615, and Department of War CA200437.
2026-04-15 | Malignant pleural mesothelioma in a young adult without asbestos exposure: a case report highlighting diagnostic pitfalls and literature review
Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy typically associated with asbestos exposure in older adults. Its occurrence in young individuals without asbestos exposure poses significant diagnostic challenges, particularly in tuberculosis-endemic regions. Case presentation: We report the case of a 23-year-old man with no history of asbestos exposure who presented with progressive pleuritic chest pain, dyspnea, fever, and weight loss. Initial evaluation suggested tuberculous pleuritis, and empirical therapy was initiated. Imaging revealed diffuse nodular pleural thickening with loculated effusion. Ultrasound-guided pleural biopsy demonstrated epithelioid MPM, confirmed by immunohistochemical positivity for calretinin and WT-1 with TTF-1 negativity. Despite supportive care, the patient experienced rapid clinical deterioration and died within 1 week of histopathological confirmation. Genetic testing for BAP1 mutation was recommended but could not be performed due to rapid disease progression. Conclusion: This case underscores the importance of considering MPM in the differential diagnosis of pleural effusion in young adults, even in the absence of asbestos exposure. Early pleural biopsy and immunohistochemical evaluation are essential to avoid diagnostic delay, particularly in tuberculosis-endemic settings.
2026-04-15 | MET amplification in diffuse pleural mesothelioma and response to savolitinib: a case report.
Pleural mesothelioma (PM) is a rare malignancy globally, most frequently associated with alterations in tumor suppressor genes such as NF2, BAP1 and CDKN2A. In contrast, mutations or amplifications of the MET gene are seldomly reported in PM. Here, we report the case of a 60-year-old East Asian male without asbestos exposure, never-smoker, diagnosed with advanced PM. The disease proved refractory to multiple lines of therapy, including platinum-based chemotherapy, immunotherapy, intrathoracic instillation and a subsequent individualized regimen comprising intraperitoneal cisplatin plus sintilimab for local disease control and potential immunomodulation synergized with oral anlotinib. Following disease progression accompanied by rapidly accumulating seroperitoneum and pelvic effusion, next-generation sequencing (NGS) of ascitic fluid revealed MET gene amplification, and the subsequent switch to savolitinib controlled the malignant ascites. Unfortunately, the patient died of sudden cardiac and respiratory arrest in December 2023. This case underscores the critical importance of comprehensive genetic testing in guiding the treatment of advanced PM, particularly after the failure of standard therapies. It illustrates that rare but actionable genomic alterations, such as MET amplification, can be identified through liquid or tissue biopsy and can inform successful targeted treatment strategies, even in a tumor type where such alterations are uncommon. Histological classification combined with molecular profiling remains pivotal for personalized oncology.
proteins
2023-03-31 | Data from Preclinical Characterization of HPN536, a Trispecific, T-Cell–Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors
<div>AbstractPurpose:<p>Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.</p>Experimental Design:<p>We designed HPN536, a 53-kDa, trispecific, T-cell–activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ϵ on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in <i>in vitro</i> assays, rodent models, and in nonhuman primates (NHP).</p>Results:<p>HPN536 binds to MSLN-expressing tumor cells and to CD3ϵ on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.</p>Conclusions:<p>HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).</p></div>
2022-09-29 | Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma.
BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.
2018-03-08 | Progress in the Management of Malignant Pleural Mesothelioma in 2017
Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.
2012-07-25 | Recombinant human endostatin (endostar) decreased recurrent ascites, pleural fluid and ascitic VEGF in a case of advanced mesothelioma
We report a case of 43-year-old male with advanced malignant mesothelioma (MM) with a large amount of fluid in the pleural and peritoneal cavity. The addition of endostar to the gemcitabine-cisplatin regimen gave a prompt and significant improvement of clinical symptoms and disappearance of ascites. The patient is still progression free after 27 months. Endostar, in combination with chemotherapy should be explored in the treatment of MM, especially its effect on pleural and ascitic fluid.
2012-06-13 | The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression
Abstract Background Transforming growth factor β induced (TGFBI) product, an extracellular matrix (ECM) protein, has been implicated as a putative tumor suppressor in recent studies. Our previous findings revealed that expression of TGFBI gene is down-regulated in a variety of cancer cell lines and clinical tissue samples. In this study, ectopic expression of TGFBI was used to ascertain its role as a tumor suppressor and to determine the underlying mechanism of mesothelioma and breast cancer. Methods Cells were stably transfected with pRc/CMV2-TGFBI and pRc/CMV2-empty vector with Lipofectamine Plus. Ectopic expression of TGFBI was quantified by using quantitative PCR and Western-blotting. Characterization of cell viability was assessed using growth curve, clonogenic survival and soft agar growth. The potential of tumor formation was evaluated by an in vivo mouse model. Cell cycle was analyzed via flow cytometry. Expressions of p21, p53, p16 and p14 were examined using Western-blotting. Senescent cells were sorted by using a Senescence β-Galactosidase Staining Kit. Telomerase activity was measured using quantitative telomerase detection kit. Results In this study, an ectopic expression of TGFBI in two types of cancer cell lines, a mesothelioma cell line NCI-H28 and a breast cancer cell line MDA-MB-231 was found to have reduced the cellular growth, plating efficiency, and anchorage-independent growth. The tumorigenicity of these cancer cell lines as determined by subcutaneous inoculation in nude mice was similarly suppressed by TGFBI expression. Likewise, TGFBI expression reduced the proportion of S-phase while increased the proportion of G1 phase in these cells. The redistribution of cell cycle phase after re-expression of TGFBI was correspondent with transiently elevated expression of p21 and p53. The activities of senescence-associated β-galactosidase and telomerase were enhanced in TGFBI-transfected cells. Conclusion Collectively, these results imply that TGFBI plays a suppressive role in the development of mesothelioma and breast cancer cells, possibly through inhibitions of cell proliferation, delaying of G1-S phase transition, and induction of senescence.
gene therapies
2024-10-06 | Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo.
Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.
2023-07-25 | Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy
Abstract Background Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. Main body Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. Conclusion OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.
2023-03-30 | Data from Malignant Pleural Mesothelioma–Targeted CREBBP/EP300 Inhibitory Protein 1 Promoter System for Gene Therapy and Virotherapy
<div>Abstract<p>Gene therapy and virotherapy are one of the approaches used to treat malignant pleural mesothelioma. To improve the efficiency of targeting malignant mesothelioma cells, we designed a novel system using the promoter of the <i>CREBBP/EP300 inhibitory protein 1</i> (<i>CRI1</i>), a gene specifically expressed in malignant pleural mesothelioma. Four tandem repeats of the CRI1 promoter (CRI1<sup>−138 4x</sup>) caused significantly high promoter activity in malignant pleural mesothelioma cells but little promoter activity in normal mesothelial cells and normal fibroblasts. The recombinant adenoviral vector expressing proapoptotic BH3-interacting death agonist or early region 1A driven by the CRI1<sup>−138 4x</sup> promoter induced cell death in malignant mesothelioma cells but not in normal cells. Moreover, these viruses showed antitumor effects in a mesothelioma xenograft mouse model. Here, we describe a novel strategy to target malignant mesothelioma using the CRI1<sup>−138 4x</sup> promoter system. [Cancer Res 2008;68(17):7120–9]</p></div>
2023-02-16 | Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma
Background The attenuated, genetically engineered vaccinia virus has been shown to be a promising oncolytic virus for the treatment of patients with solid tumors, through both direct cytotoxic and immune-activating effects. Whereas systemically administered oncolytic viruses can be neutralized by pre-existing antibodies, locoregionally administered viruses can infect tumor cells and generate immune responses. We conducted a phase I clinical trial to investigate the safety, feasibility and immune activating effects of intrapleural administration of oncolytic vaccinia virus (NCT01766739). Methods Eighteen patients with malignant pleural effusion due to either malignant pleural mesothelioma or metastatic disease (non-small cell lung cancer or breast cancer) underwent intrapleural administration of the oncolytic vaccinia virus using a dose-escalating method, following drainage of malignant pleural effusion. The primary objective of this trial was to determine a recommended dose of attenuated vaccinia virus. The secondary objectives were to assess feasibility, safety and tolerability; evaluate viral presence in the tumor and serum as well as viral shedding in pleural fluid, sputum, and urine; and evaluate anti-vaccinia virus immune response. Correlative analyses were performed on body fluids, peripheral blood, and tumor specimens obtained from pre- and post-treatment timepoints. Results Treatment with attenuated vaccinia virus at the dose of 1.00E+07 plaque-forming units (PFU) to 6.00E+09 PFU was feasible and safe, with no treatment-associated mortalities or dose-limiting toxicities. Vaccinia virus was detectable in tumor cells 2-5 days post-treatment, and treatment was associated with a decrease in tumor cell density and an increase in immune cell density as assessed by a pathologist blinded to the clinical observations. An increase in both effector (CD8+, NK, cytotoxic cells) and suppressor (Tregs) immune cell populations was observed following treatment. Dendritic cell and neutrophil populations were also increased, and immune effector and immune checkpoint proteins (granzyme B, perforin, PD-1, PD-L1, and PD-L2) and cytokines (IFN-γ, TNF-α, TGFβ1 and RANTES) were upregulated. Conclusion The intrapleural administration of oncolytic vaccinia viral therapy is safe and feasible and generates regional immune response without overt systemic symptoms. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT01766739 , identifier NCT01766739.
2020-01-13 | Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus
IntroductionOncolytic immunotherapy is based on the use of nonpathogenic replicative oncolytic viruses that infect and kill tumor cells exclusively. Recently, we found that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN-I) response in tumor cells.MethodsIn this study, we studied three independent human MPM bio-collections to identify the defects in the IFN-I responses in tumor cells.ResultsWe show that the most frequent defect is the homozygous deletions (HDs) of all the 14 IFN-I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HDs occur together with the HDs of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN-I−/− MPM cell lines develop a partial and weak IFN-I response when they are exposed to the virus compared with that of normal cells and MV-resistant MPM cell lines. This response consists of the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN-I. In addition, the IFN-I−/− MPM cell lines infected by MV also develop a pro-inflammatory response associated with stress of the endoplasmic reticulum.ConclusionOur study emphasizes the link between HDs of IFN-I encoding genes and the CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.
antibodies
2026-06-21 | Amivantamab induces immune-mediated cytotoxicity in mesothelioma via EGFR and MET engagement.
Diffuse pleural mesothelioma (DPM) is a lethal malignancy with no approved therapies directly targeting tumor cells. Based on reports that epidermal growth factor receptor (EGFR) and MET proto-oncogene (MET) are frequently expressed in DPM, we sought to systematically assess their co-expression and determine the preclinical activity of amivantamab, a bispecific antibody that targets EGFR and MET. We evaluated EGFR and MET expression in patient cohorts and cell lines using transcriptomic analysis, immunohistochemistry, and biochemical assays. The mechanistic actions of amivantamab, including receptor internalization, signaling blockade, and immune-mediated cytotoxicity, were assessed using in vitro co-culture systems with peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. In vivo efficacy was evaluated in mesothelioma patient-derived xenograft (PDX) models using immunodeficient mice reconstituted with human NK cells. Transcriptomic and single-cell RNA sequencing analyses of DPM patient cohorts revealed frequent co-expression of EGFR and MET, predominantly in malignant cells. Immunohistochemical analyses confirmed EGFR and MET protein expression across mesothelioma histologic subtypes. In vitro, amivantamab preferentially bound to DPM cells, inhibited ligand-induced EGFR and MET signaling, and promoted receptor internalization. Co-culture experiments demonstrated that amivantamab induced dose-dependent cytotoxicity via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In multiple mesothelioma PDX models, the combination of amivantamab and NK cells significantly reduced tumor growth without overt toxicity. Amivantamab demonstrates robust preclinical antitumor activity in mesothelioma primarily through innate immune-mediated cytotoxicity associated with EGFR and MET engagement. These findings support the clinical evaluation of bispecific EGFR/MET-targeting antibodies in mesothelioma.
2026-04-03 | Abstract 109: Integrative analyses of the cfDNA fragmentome and TCR repertoires capture chemo-immunotherapy response in diffuse pleural mesothelioma.
Abstract Background: Immunotherapy-containing therapies have shown promise for patients with unresectable diffuse pleural mesothelioma (DPM), yet there are no reliable strategies to monitor therapy response. By expanding the compendium of cancer-associated alterations profiled, including genome-wide fragmentation patterns, cell-free DNA (cfDNA) whole genome sequencing (WGS) enables tracking of tumor dynamics. In tandem, while understudied, T cell clone dynamics may be informative in capturing early immunotherapy response. Methods: Using 314 tumor and peripheral blood biospecimes, we analyzed serial plasma cfDNA samples (n=135) from 55 patients with unresectable DPM, who received durvalumab with platinum-based chemotherapy (NCT02899195). Following cfDNA extraction and genomic library preparation, cfDNA at baseline (C1D1), Cycle 2 Day 1 (C2D1), and Cycle 5 Day 1 (C5D1) underwent low-coverage (1-2x) whole genome sequencing. Tumor- and mutation-naive estimates of tumor fraction were derived by applying the DELFI tumor score (DELFI-TS) model, which integrates genome-wide fragmentation patterns and chromosomal arm aneuploidy. In parallel, we performed TCR Vβ CDR3 next-generation sequencing on tumor (n=43) and peripheral serial blood (n=136) samples. The TCR repertoire was characterized using clonality, TCR clonotype/cluster dynamics, and the Morisita-Horn similarity index to assess repertoire similarity across samples. Clinical outcomes were assessed by radiographic response, progression-free (PFS), and overall survival (OS). Results: Patients with distant metastasis (M1) had higher DELFI-TS levels (p=0.038). At baseline, DELFI-TS levels were numerically higher for radiographic non-responders (SD/PD) vs responders (CR/PR). Using the 92th percentile of DELFI-TS in non-cancer cfDNA control samples to determine the limit of blank, patients with detectable baseline DELFI-TS (ctDNA+) had shorter PFS and OS (log-rank p<0.001). Patients that attained a radiographic response had more clonal peripheral TCR repertoires at both baseline and on-therapy timepoints compared to non-responders (p=0.037 at C1D1; p=0.007 at C2D1; p=0.042 at C5D1). Morisita-Horn similarity between C1D1 and on-therapy was lower in non-responders than responders (p=0.019 for C1D1 vs C2D1; p=0.036 for C1D1 vs C5D1). In contrast, a more diverse intra-tumoral TCR repertoire was noted for patients with an OS of 12 or more months (p=0.018). Conclusions: Our findings provide proof-of-concept that cfDNA fragmentomic analyses can quantify pre-treatment cfDNA tumor fraction that may capture clinical outcomes with chemo-immunotherapy response for patients with DPM. Longitudinal analyses of peripheral TCR repertoires can further differentiate responding from non-responding DPM, supporting the notion that joint analyses may more accurately capture immunotherapy response. Citation Format: Jinny Huang, Jennifer Li, James R. White, Shashikant Koul, Gavin Pereira, Nisha Rao, Jennie Yao, Julie R. Brahmer, Robert B. Scharpf, Rachel Karchin, Victor E. Velculescu, Zhouxin Sun, Suresh S. Ramalingam, Patrick M. Forde, Noushin Niknafs, Valsamo (Elsa) K. Anagnostou. Integrative analyses of the cfDNA fragmentome and TCR repertoires capture chemo-immunotherapy response in diffuse pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 109.
2026-04-03 | Abstract 5547: Enhancing antibody-dependent cellular cytotoxicityin mesothelioma through concurrent EGFR and MET targeting withamivantamab
Abstract Background: Diffuse pleural mesothelioma (DPM) is a highly aggressive malignancy with limited treatment options and poor prognosis. Although immune checkpoint inhibitors have improved outcomes, particularly for non-epithelioid subtypes, there remains no approved targeted therapy for mesothelioma. EGFR and MET are receptor tyrosine kinases frequently overexpressed in DPM, suggesting susceptibility to targeted antibody therapy. Amivantamab is a bispecific EGFR/MET antibody, originally developed for EGFR-mutant lung cancer, that blocks growth signals and engaging immune mechanisms. Given the high levels of EGFR and MET expression in mesothelioma, we evaluated the therapeutic potential of amivantamab in preclinical models. Methods: EGFR and MET transcript levels in DPM were analyzed using TCGA. Eight human mesothelioma cell lines were assessed by Western blotting and flow cytometry. Amivantamab binding, internalization, and signaling inhibition were examined using flow cytometry, confocal microscopy, and ligand-stimulated phosphorylation assays. Cytotoxicity and immune-effector activity were quantified using PBMCs, NK cells, and monocytes from healthy donors, along with an ADCC reporter assay. In vivo efficacy was tested in a DPM patient-derived xenograft (PDX) model in NOD/SCID-γ (NSG) mice supplemented with human NK cells and treated with amivantamab or control IgG. Results: TCGA analysis showed frequent EGFR/MET co-expression in DPM. Mesothelioma cell lines expressed higher EGFR and MET levels compared with mesothelial cells. Amivantamab strongly bound both receptors, induced receptor internalization, and inhibited EGF- and HGF-stimulated phosphorylation of EGFR, MET, and downstream AKT/ERK signaling. Direct cytotoxicity was minimal; however, the addition of PBMCs or NK cells resulted in robust, dose-dependent tumor cell killing consistent with antibody-dependent cellular cytotoxicity (ADCC). Reporter assays demonstrated 7-11-fold Fcγ receptor activation in tumor cells compared with ∼2-fold activation in non-malignant mesothelial cells. Co-culture with monocytes revealed amivantamab-induced trogocytosis, evidenced by loss of EGFR and MET from tumor-cell membranes. In the DPM PDX model, amivantamab produced 89.1% tumor-growth inhibition (TGI) relative to controls (P < 0.0001), with no overt toxicity observed in treated mice. Conclusions: Dual EGFR/MET targeting with amivantamab produced potent antitumor effects in mesothelioma through coordinated receptor-signaling blockade, ADCC, and monocyte-mediated trogocytosis. These results support amivantamab as a promising targeted therapeutic strategy for EGFR/MET-positive DPM, particularly epithelioid subtypes that currently derive limited benefit from immunotherapy. Citation Format: Shinichiro Suzuki, Kaushal Parikh, Ezequiel Tolosa, Kuan-Li Wu, Jennifer Ayers-Ringler, Lin Yang, Katherine E. Smith, Farhad Kosari, Aaron S. Mansfield, . Enhancing antibody-dependent cellular cytotoxicityin mesothelioma through concurrent EGFR and MET targeting withamivantamab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5547.
2025-12-30 | Determinants of Response to Immune Checkpoint Blockade in Pleural Mesothelioma: Molecular, Immunological, and Clinical Perspectives.
Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)-notably the combination of anti-PD-1 and anti-CTLA-4 therapies-clinical responses remain variable and overall survival gains modest. Consequently, there is an urgent need for multidimensional biomarkers and adaptive trial designs to unravel the complexity of PM immune biology. This review provides a comprehensive overview of current evidence on how histological subtypes (epithelioid vs. non-epithelioid) influence ICB efficacy, highlighting distinct genetic landscapes (e.g., BAP1, CDKN2A, NF2 mutations) and tumor microenvironment (TME) features, including immune infiltration patterns and PD-L1 or VISTA expression, that underlie differential responses. We further examine intrinsic tumor factors-such as mutational burden and checkpoint ligand expression-and extrinsic determinants, including immune cell composition, stromal architecture, patient immune status, and microbiota, as modulators of immunotherapy outcomes. We also discuss the rationale behind emerging strategies designed to enhance ICB efficacy, currently under clinical evaluation. These include combination regimens with chemotherapy, radiotherapy, surgery, epigenetic modulators, anti-angiogenic agents, and novel immunotherapies such as next-generation checkpoint inhibitors (LAG-3, VISTA), immune-suppressive cell-targeting agents, vaccines, cell-based therapies, and oncolytic viruses. Collectively, these advancements underscore the importance of integrating histological classification with molecular and microenvironmental profiling to refine patient selection and guide the development of combination strategies aimed at transforming "cold" mesotheliomas into "hot," immune-responsive tumors, thereby enhancing the efficacy of ICB.
2025-11-01 | 510 Dynamic tumor and immune response to neoadjuvant nivolumab with chemotherapy in diffuse pleural mesothelioma
Background Diffuse pleural mesothelioma (DPM) is an aggressive malignancy with poor outcomes even in potentially resectable disease. With an evolving understanding of the role of pleurectomy/decortication (P/D) in patients with resectable disease, the need to optimize and improve upfront therapies is more urgent. Here, we report on transcriptional and spatial correlates of progression free survival from this single institution prospective pilot study of nivolumab with platinum (cisplatin/carboplatin) and pemetrexed prior to P/D (2 cycles) for patients with resectable DPM ( NCT04162015).Methods To comprehensively assess tumor and immune microenvironment changes after immunotherapy with chemotherapy in DPM, single cell RNAseq was performed on 20 resection specimens from 16 patients with available material, including three patients with matched pre/post resection specimens. In addition, peripheral blood mononuclear cell (PBMC) from pre/post treatment, whole exome sequencing, and spatial analyses were studied to comprehensively understand treatment resistance to immunotherapy with chemotherapy in this rare tumor type. Here we report on the transcriptional and spatial tumor microenvironment changes that correlate with response after treatment from generating the largest cohort of DPM resection specimens analyzed by single-cell RNAseq.Results 22 patients received neoadjuvant chemo-immunotherapy and 19 underwent attempted P/D (2 progressed and 1 declined surgery) within 30 days of the planned resection date. Of the 19 patients that went for P/D, the median OS from the start of neoadjuvant therapy was 34mos with a progression free survival (PFS) of 14mos (median follow-up: 32mos). We discover that after two cycles of chemotherapy with nivolumab long-term responders (PFS>12 months) have a tumor microenvironment enriched by lymphocytes (CD4+ and CD8+ T cells as well as NK cells) while short-term responders had an abundance of myeloid cells. Short term responders had a clear enrichment of an IFN-responsive signature in tumor cells. Further analysis revealed that enrichment of clonally expanded CD8+ tumor reactive T-cells with exhaustion features, GZMK+ effector memory CD8+ T cells, and a shift from monocytes to APOE+ macrophages were features of the tumor immune compartment in long term responders. Moreover, we discover that DPM cells exist on a phenotypic-continuum between mesothelial-like and fibroblast-like states. Leveraging spatial transcriptomics, we find fibroblast-like tumor cells occupy spatially distinct tumor regions characterized by poor immune infiltrate and high TGFβ-signatures.Conclusions This in-depth characterization of the largest cohort of DPM resection specimens analyzed at a single cell level after neoadjuvant treatment provides foundational insights to characterize DPM responders to chemo-IO and support future therapeutic development.
other
2026-04-03 | Abstract 2052: miR-342-5p: A promising tumor suppressor in diffuse pleural mesothelioma.
Abstract Diffuse pleural mesothelioma (DPM) is an incurable, aggressive neoplasm with limited therapies. Moving beyond conventional approaches, we posit that microRNAs (miRNA), short, non-coding RNA that coherently regulate gene expression, can uniquely disrupt the molecular networks involved in DPM. In this study, we identified miR-342-5p as a novel DPM-associated miRNA. We used a human miRNA mimic library to screen for miRNAs with antiproliferative effects on a panel of DPM cell lines. Among the most potent candidates was miR-342-5p. We profiled the downregulation of miR-342-5p in DPM patient specimens compared to normal pleura (Normal=22, Tumor=50). TCGA-MESO analysis revealed that miR-342-5p downregulation is significantly associated with poor survival outcomes. Our results demonstrated that the re-expression of miR-342-5p significantly impaired DPM cell viability, reduced 2D colony foci formation, and inhibited anchorage-independent cell growth in soft-agar and sphere assays. Additionally, Annexin-V assays showed a significant increase in early and late apoptotic cells in miR-342-5p transfected DPM cells compared to controls. Furthermore, we confirmed the induction of apoptosis in miR-342-5p-treated DPM cells through PARP cleavage and the activation of caspase-3/7. Importantly, no significant biological effects were observed when normal human mesothelial cells (NP1 line) were treated with miR-342-5p. Next, we performed a Biotin-miRNA (Bi-miR) pull-down assay, a direct binding assay in which a biotin-tagged miR-342-5p probe captures its associated mRNA transcripts in a pooled lysate. Then, RNA-seq analysis is conducted to identify direct target genes associated with apoptosis and cell death pathways in DPM. We identified the top transcripts targeted by miR-342-5p that are also involved in its tumor-suppressive activity in DPM. Overall, our findings highlight the tumor suppressive effects and therapeutic potential of miR-342-5p for DPM treatment. Citation Format: So-Hyun Yoon, Anand Singh, Nathanael Pruett, Vivek Singh, Smrity Sahu, Yelixza Avila, Chuong Hoang. miR-342-5p: A promising tumor suppressor in diffuse pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2052.
2023-08-07 | Coengineering specificity, safety, and function into T cells for cancer immunotherapy
Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.
2023-03-31 | Data from Enhanced Antitumor Therapy by Inhibition of p21<sup>waf1</sup> in Human Malignant Mesothelioma
<div>Abstract<p><b>Purpose:</b> The p21 cyclin-dependent kinase inhibitor was frequently expressed in human malignant pleural mesothelioma (MPM) tissues as well as cell lines. Recent data indicate that p21 keeps tumor cells alive after DNA damage, favoring a survival advantage. In this study, we assessed the possibility of p21 suppression as a therapeutic target for MPM.</p><p><b>Experimental Design:</b> We established two different MPM-derived (from H28 and H2052 cells) subclones using vector-based short hairpin RNA (shRNA). Then, chemosensitivity against low doses of antineoplastic DNA-damaging agents was investigated by colony formation assays, and furthermore, the type of cell response induced by these drugs was analyzed. To examine the effect of p21 shRNA on chemosensitivity <i>in vivo</i>, tumor formation assays in nude mice were done.</p><p><b>Results:</b> In colony formation assay, the IC<sub>50</sub> of doxorubicin was 33 ± 3.0 nmol/L in p21 shRNA-transfected cells with respect to 125 ± 10 nmol/L of control vector–transfected cells. This enhancement of growth inhibition was achieved by converting a senescence-like growth arrest to apoptosis in response to doxorubicin, etoposide, and CPT11. In the <i>in vivo</i> assays, CPT11 and loss-of-expression of p21 in combination led to considerable suppression of tumor growth associated with a substantially enhanced apoptotic response, whereas CPT11 alone was ineffective at inducing these responses.</p><p><b>Conclusions:</b> These results indicated that p21 might play an important role in chemosensitivity to anticancer agents, and the suppression of its expression might be a potential therapeutic target for MPM.</p></div>
2022-11-26 | The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Drug Target Evaluation
Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors BAP1, NF2 and P16 may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses. Ten cell lines, representing the spectrum of histological subtypes and tumour suppressor status, were dual labelled for fluorescence/bioluminescence imaging and implanted on the CAM at E7. Bioluminescence was used to assess viability of primary tumours, which were excised at E14 for immunohistological staining or real-time PCR. All MPM cell lines engrafted efficiently forming vascularised nodules, however their size, morphology and interaction with chick cells varied. MPM phenotypes including local invasion, fibroblast recruitment, tumour angiogenesis and vascular remodelling were evident. Bioluminescence imaging could be used to reliably estimate tumour burden pre- and post-treatment, correlating with tumour weight and Ki-67 staining. In conclusion, MPM-CAM models recapitulate important features of the disease and are suitable to assess drug targets using a broad range of MPM cell lines that allow histological or genetic stratification. They are amenable to multi-modal imaging, potentially offering a time and cost-efficient, 3Rs-compliant alternative to rodent xenograft models to prioritise candidate compounds from in vitro studies.
2022-09-20 | The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Target and Compound Evaluation
Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors BAP1, NF2 and P16 may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses. Ten cell lines, representing the spectrum of histological subtypes and tumour suppressor status, were dual labelled for fluorescence/bioluminescence imaging and implanted on the CAM at E7. Bioluminescence was used to assess viability of primary tumours, which were excised at E14 for immunohistological staining or real-time PCR. All MPM cell lines engrafted efficiently forming vascularised nodules, however their size, morphology and interaction with chick cells varied. MPM phenotypes including local invasion, fibroblast recruitment, tumour angiogenesis and vascular remodelling were evident. Bioluminescence imaging could be used to reliably estimate tumour burden pre- and post-treatment, correlating with tumour weight and Ki-67 staining. In conclusion, MPM-CAM models recapitulate important features of the disease and are suitable to assess therapies using a broad range of MPM cell lines that allow histological or genetic stratification. They are amenable to multi-modal imaging, offering a time and cost-efficient, 3Rs-compliant alternative to rodent xenograft models to prioritise candidate compounds from in vitro studies.
small molecules
2026-09-24 | Cytotoxic Microspinosamides from the Marine Sponge Geodia microspinosa That Decrease Diffuse Pleural Mesothelioma Viability.
A fraction from an extract of the marine sponge Geodia microspinosa was identified as active in a high-throughput screen for molecules that impair the viability of diffuse pleural mesothelioma (DPM) cell lines. Bioassay-guided isolation led to the identification of microspinosamides B and D, and a new artifact, microspinosamide C, together with two previously reported analogues, microspinosamide and polydiscamide B, as the active principles. Their planar structures were solved by NMR and HRESIMS analyses, while advanced Marfey's reaction, ROESY, and ECD were used for the establishment of their absolute configurations. All pure metabolites demonstrated low micromolar potency for the reduction in viability of the DPM cell lines.
2026-08-24 | [Ileal Perforation Caused by Pleural Mesothelioma-related Small Intestinal Involvement: A Case Report and Literature Review].
Pleural mesothelioma (PM) usually manifests as local intrathoracic invasion, and small intestinal involvement is rare. A 37-year-old man with initially diagnosed stage IV diffuse PM and no definite history of asbestos exposure or other specific occupational or environmental exposure except for long-term smoking was reported. After first-line treatment with Pemetrexed, Carboplatin and Bevacizumab, the disease remained stable. However, acute abdomen occurred during maintenance therapy, and emergency surgery confirmed terminal ileal perforation. Postoperative pathology suggested PM-related ileal involvement/metastatic involvement, with a higher Ki-67 proliferation index than that of the primary lesion. Because only perforation repair rather than segmental bowel resection was performed, the available pathological material could not determine whether full-thickness bowel-wall involvement was present or the direction of tumor invasion. Imaging findings, intraoperative findings and pathological results did not support primary peritoneal mesothelioma or direct contiguous invasion of the ileum by the diaphragmatic lesion; however, microscopic peritoneal dissemination with secondary bowel-wall involvement could not be completely excluded. The aim of this report, together with literature review, is to summarize the diagnostic challenges, management strategies and clinical implications of PM-related small intestinal involvement. .
2026-05-29 | Loss of tumor suppressor NF2 mediates resistance to CAR T cell and anti-PD-1 therapy: Strategies to restore immunotherapy sensitivity.
Investigating the biological mechanisms of acquired resistance to immunotherapy remains a necessity for effective treatment of solid tumors. Diffuse pleural mesothelioma (DPM) tumors, from immunocompetent and immunodeficient mouse models with acquired resistance to chimeric antigen receptor (CAR) T cell therapy were analyzed using flow cytometry, immunofluorescence, and ELISA. The interplay between genetic alterations in the cancer cell and site-specific tumor immune microenvironment (TIME) was characterized; therapies to reverse immunotherapy resistance were investigated. Analysis of tumors with acquired resistance to CAR T cell therapy demonstrated lower expression of tumor suppressor NF2. Enforced depletion of NF2 promoted resistance to CAR T cell and anti-PD-1 therapy in DPM but not in heterotopic subcutaneous tumors. Loss of NF2 was associated with accumulation of immunosuppressive complement receptor of immunoglobulin superfamily (CRIg)+ macrophages in pleural tumors, which was dependent on tumor-secreted chemokines and retinoic acid. Ablation of chemokines or pharmacologic inhibition of retinoic acid or the Hippo pathway by use of TEAD inhibitors restored sensitivity to CAR T cell therapy. Correspondingly, in two independent cohorts of patients, DPM tumors with NF2 copy-number loss, but not mutations, were associated with higher infiltration of M2 macrophages, lower infiltration and function of CD8 T cells, and an anti-PD-1-resistant gene signature. Our study uncovers a previously unknown mechanism of resistance to immunotherapy by identifying the dynamic interplay between cancer cell genetic alterations and the TIME. This research was funded in part through the NCI UG3CA290241, R01CA292664, R01CA235667, R01CA236615, and Department of War CA200437.
2026-04-15 | Malignant pleural mesothelioma in a young adult without asbestos exposure: a case report highlighting diagnostic pitfalls and literature review
Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive malignancy typically associated with asbestos exposure in older adults. Its occurrence in young individuals without asbestos exposure poses significant diagnostic challenges, particularly in tuberculosis-endemic regions. Case presentation: We report the case of a 23-year-old man with no history of asbestos exposure who presented with progressive pleuritic chest pain, dyspnea, fever, and weight loss. Initial evaluation suggested tuberculous pleuritis, and empirical therapy was initiated. Imaging revealed diffuse nodular pleural thickening with loculated effusion. Ultrasound-guided pleural biopsy demonstrated epithelioid MPM, confirmed by immunohistochemical positivity for calretinin and WT-1 with TTF-1 negativity. Despite supportive care, the patient experienced rapid clinical deterioration and died within 1 week of histopathological confirmation. Genetic testing for BAP1 mutation was recommended but could not be performed due to rapid disease progression. Conclusion: This case underscores the importance of considering MPM in the differential diagnosis of pleural effusion in young adults, even in the absence of asbestos exposure. Early pleural biopsy and immunohistochemical evaluation are essential to avoid diagnostic delay, particularly in tuberculosis-endemic settings.
2026-04-15 | MET amplification in diffuse pleural mesothelioma and response to savolitinib: a case report.
Pleural mesothelioma (PM) is a rare malignancy globally, most frequently associated with alterations in tumor suppressor genes such as NF2, BAP1 and CDKN2A. In contrast, mutations or amplifications of the MET gene are seldomly reported in PM. Here, we report the case of a 60-year-old East Asian male without asbestos exposure, never-smoker, diagnosed with advanced PM. The disease proved refractory to multiple lines of therapy, including platinum-based chemotherapy, immunotherapy, intrathoracic instillation and a subsequent individualized regimen comprising intraperitoneal cisplatin plus sintilimab for local disease control and potential immunomodulation synergized with oral anlotinib. Following disease progression accompanied by rapidly accumulating seroperitoneum and pelvic effusion, next-generation sequencing (NGS) of ascitic fluid revealed MET gene amplification, and the subsequent switch to savolitinib controlled the malignant ascites. Unfortunately, the patient died of sudden cardiac and respiratory arrest in December 2023. This case underscores the critical importance of comprehensive genetic testing in guiding the treatment of advanced PM, particularly after the failure of standard therapies. It illustrates that rare but actionable genomic alterations, such as MET amplification, can be identified through liquid or tissue biopsy and can inform successful targeted treatment strategies, even in a tumor type where such alterations are uncommon. Histological classification combined with molecular profiling remains pivotal for personalized oncology.
proteins
2023-03-31 | Data from Preclinical Characterization of HPN536, a Trispecific, T-Cell–Activating Protein Construct for the Treatment of Mesothelin-Expressing Solid Tumors
<div>AbstractPurpose:<p>Mesothelin (MSLN) is a glycophosphatidylinositol-linked tumor antigen overexpressed in a variety of malignancies, including ovarian, pancreatic, lung, and triple-negative breast cancer. Early signs of clinical efficacy with MSLN-targeting agents have validated MSLN as a promising target for therapeutic intervention, but therapies with improved efficacy are still needed to address the significant unmet medical need posed by MSLN-expressing cancers.</p>Experimental Design:<p>We designed HPN536, a 53-kDa, trispecific, T-cell–activating protein-based construct, which binds to MSLN-expressing tumor cells, CD3ϵ on T cells, and to serum albumin. Experiments were conducted to assess the potency, activity, and half-life of HPN536 in <i>in vitro</i> assays, rodent models, and in nonhuman primates (NHP).</p>Results:<p>HPN536 binds to MSLN-expressing tumor cells and to CD3ϵ on T cells, leading to T-cell activation and potent redirected target cell lysis. A third domain of HPN536 binds to serum albumin for extension of plasma half-life. In cynomolgus monkeys, HPN536 at doses ranging from 0.1 to 10 mg/kg demonstrated MSLN-dependent pharmacologic activity, was well tolerated, and showed pharmacokinetics in support of weekly dosing in humans.</p>Conclusions:<p>HPN536 is potent, is well tolerated, and exhibits extended half-life in NHPs. It is currently in phase I clinical testing in patients with MSLN-expressing malignancies (NCT03872206).</p></div>
2022-09-29 | Clinical and molecular validation of BAP1, MTAP, P53, and Merlin immunohistochemistry in diagnosis of pleural mesothelioma.
BAP1 and MTAP immunostains play an important role in diagnosis of mesothelioma, but additional markers are needed to increase sensitivity. We analyzed 84 pleural mesotheliomas (51 epithelioid, 27 biphasic, 6 sarcomatoid) by a hybrid-capture next-generation sequencing (NGS) panel including complete coverage of coding and splicing regions for BAP1, CDKN2A/MTAP, NF2, and TP53 and correlated molecular findings with diagnostic immunostains for BAP1, MTAP, Merlin, and p53, respectively. Fifty-seven reactive mesothelial proliferations served as benign comparators. Loss of BAP1, MTAP, and Merlin protein expression were, respectively, 54%, 46%, and 52% sensitive and 100% specific for mesothelioma. Two-marker immunopanels of BAP1 + MTAP, BAP1 + Merlin, and MTAP + Merlin were 79%, 85%, and 71% sensitive for mesothelioma, while a three-marker immunopanel of BAP1 + MTAP + Merlin was 90% sensitive. Diffuse (mutant-pattern) p53 immunostaining was seen in only 6 (7%) tumors but represented the only immunohistochemical abnormality in 2 cases. Null-pattern p53 was not specific for malignancy. An immunopanel of BAP1 + MTAP + Merlin + p53 was 93% sensitive for mesothelioma, and panel NGS detected a pathogenic alteration in BAP1, MTAP, NF2, and/or TP53 in 95%. Together, 83 (99%) of 84 tumors showed a diagnostic alteration by either immunohistochemistry or panel NGS. Adding Merlin to the standard BAP1 + MTAP immunopanel increases sensitivity for mesothelioma without sacrificing specificity. p53 immunohistochemistry and panel NGS with complete coverage of BAP1, CDKN2A/MTAP, TP53, and NF2 may be useful in diagnostically challenging cases.
2018-03-08 | Progress in the Management of Malignant Pleural Mesothelioma in 2017
Malignant pleural mesothelioma (MPM) is an uncommon, almost universally fatal, asbestos-induced malignancy. New and effective strategies for diagnosis, prognostication, and treatment are urgently needed. Herein we review the advances in MPM achieved in 2017. Whereas recent epidemiological data demonstrated that the incidence of MPM-related death continued to increase in United States between 2009 and 2015, new insight into the molecular pathogenesis and the immunological tumor microenvironment of MPM, for example, regarding the role of BRCA1 associated protein 1 and the expression programmed death receptor ligand 1, are highlighting new potential therapeutic strategies. Furthermore, there continues to be an ever-expanding number of clinical studies investigating systemic therapies for MPM. These trials are primarily focused on immunotherapy using immune checkpoint inhibitors alone or in combination with other immunotherapies and nonimmunotherapies. In addition, other promising targeted therapies, including pegylated adenosine deiminase (ADI-PEG20), which focuses on argininosuccinate synthase 1-deficient tumors, and tazemetostat, an enhancer of zeste 2 polycomb repressive complex 2 subunit inhibitor of BRCA1 associated protein 1 gene (BAP1)-deficient tumors, are currently being explored.
2012-07-25 | Recombinant human endostatin (endostar) decreased recurrent ascites, pleural fluid and ascitic VEGF in a case of advanced mesothelioma
We report a case of 43-year-old male with advanced malignant mesothelioma (MM) with a large amount of fluid in the pleural and peritoneal cavity. The addition of endostar to the gemcitabine-cisplatin regimen gave a prompt and significant improvement of clinical symptoms and disappearance of ascites. The patient is still progression free after 27 months. Endostar, in combination with chemotherapy should be explored in the treatment of MM, especially its effect on pleural and ascitic fluid.
2012-06-13 | The role of TGFBI in mesothelioma and breast cancer: association with tumor suppression
Abstract Background Transforming growth factor β induced (TGFBI) product, an extracellular matrix (ECM) protein, has been implicated as a putative tumor suppressor in recent studies. Our previous findings revealed that expression of TGFBI gene is down-regulated in a variety of cancer cell lines and clinical tissue samples. In this study, ectopic expression of TGFBI was used to ascertain its role as a tumor suppressor and to determine the underlying mechanism of mesothelioma and breast cancer. Methods Cells were stably transfected with pRc/CMV2-TGFBI and pRc/CMV2-empty vector with Lipofectamine Plus. Ectopic expression of TGFBI was quantified by using quantitative PCR and Western-blotting. Characterization of cell viability was assessed using growth curve, clonogenic survival and soft agar growth. The potential of tumor formation was evaluated by an in vivo mouse model. Cell cycle was analyzed via flow cytometry. Expressions of p21, p53, p16 and p14 were examined using Western-blotting. Senescent cells were sorted by using a Senescence β-Galactosidase Staining Kit. Telomerase activity was measured using quantitative telomerase detection kit. Results In this study, an ectopic expression of TGFBI in two types of cancer cell lines, a mesothelioma cell line NCI-H28 and a breast cancer cell line MDA-MB-231 was found to have reduced the cellular growth, plating efficiency, and anchorage-independent growth. The tumorigenicity of these cancer cell lines as determined by subcutaneous inoculation in nude mice was similarly suppressed by TGFBI expression. Likewise, TGFBI expression reduced the proportion of S-phase while increased the proportion of G1 phase in these cells. The redistribution of cell cycle phase after re-expression of TGFBI was correspondent with transiently elevated expression of p21 and p53. The activities of senescence-associated β-galactosidase and telomerase were enhanced in TGFBI-transfected cells. Conclusion Collectively, these results imply that TGFBI plays a suppressive role in the development of mesothelioma and breast cancer cells, possibly through inhibitions of cell proliferation, delaying of G1-S phase transition, and induction of senescence.
gene therapies
2024-10-06 | Gene therapy for diffuse pleural mesotheliomas in preclinical models by concurrent expression of NF2 and SuperHippo.
Diffuse pleural mesothelioma (DPM) is a lethal cancer with a poor prognosis and limited treatment options. The Hippo signaling pathway genes, such as NF2 and LATS1/2, are frequently mutated in DPM, indicating a tumor suppressor role in the development of DPM. Here, we show that in DPM cell lines lacking NF2 and in mice with a conditional Nf2 knockout, downregulation of WWC proteins, another family of Hippo pathway regulators, accelerates DPM progression. Conversely, the expression of SuperHippo, a WWC-derived minigene, effectively enhances Hippo signaling and suppresses DPM development. Moreover, the adeno-associated virus serotype 6 (AAV6) has been engineered to deliver both NF2 and SuperHippo genes into mesothelial cells, which substantially impedes tumor growth in xenograft and genetic DPM models and prolongs the median survival of mice. These findings serve as a proof of concept for the potential use of gene therapy targeting the Hippo pathway to treat DPM.
2023-07-25 | Oncolytic virotherapy evolved into the fourth generation as tumor immunotherapy
Abstract Background Oncolytic virotherapy (OVT) is a promising anti-tumor modality that utilizes oncolytic viruses (OVs) to preferentially attack cancers rather than normal tissues. With the understanding particularly in the characteristics of viruses and tumor cells, numerous innovative OVs have been engineered to conquer cancers, such as Talimogene Laherparepvec (T-VEC) and tasadenoturev (DNX-2401). However, the therapeutic safety and efficacy must be further optimized and balanced to ensure the superior safe and efficient OVT in clinics, and reasonable combination therapy strategies are also important challenges worthy to be explored. Main body Here we provided a critical review of the development history and status of OVT, emphasizing the mechanisms of enhancing both safety and efficacy. We propose that oncolytic virotherapy has evolved into the fourth generation as tumor immunotherapy. Particularly, to arouse T cells by designing OVs expressing bi-specific T cell activator (BiTA) is a promising strategy of killing two birds with one stone. Amazing combination of therapeutic strategies of OVs and immune cells confers immense potential for managing cancers. Moreover, the attractive preclinical OVT addressed recently, and the OVT in clinical trials were systematically reviewed. Conclusion OVs, which are advancing into clinical trials, are being envisioned as the frontier clinical anti-tumor agents coming soon.
2023-03-30 | Data from Malignant Pleural Mesothelioma–Targeted CREBBP/EP300 Inhibitory Protein 1 Promoter System for Gene Therapy and Virotherapy
<div>Abstract<p>Gene therapy and virotherapy are one of the approaches used to treat malignant pleural mesothelioma. To improve the efficiency of targeting malignant mesothelioma cells, we designed a novel system using the promoter of the <i>CREBBP/EP300 inhibitory protein 1</i> (<i>CRI1</i>), a gene specifically expressed in malignant pleural mesothelioma. Four tandem repeats of the CRI1 promoter (CRI1<sup>−138 4x</sup>) caused significantly high promoter activity in malignant pleural mesothelioma cells but little promoter activity in normal mesothelial cells and normal fibroblasts. The recombinant adenoviral vector expressing proapoptotic BH3-interacting death agonist or early region 1A driven by the CRI1<sup>−138 4x</sup> promoter induced cell death in malignant mesothelioma cells but not in normal cells. Moreover, these viruses showed antitumor effects in a mesothelioma xenograft mouse model. Here, we describe a novel strategy to target malignant mesothelioma using the CRI1<sup>−138 4x</sup> promoter system. [Cancer Res 2008;68(17):7120–9]</p></div>
2023-02-16 | Correlative analysis from a phase I clinical trial of intrapleural administration of oncolytic vaccinia virus (Olvi-vec) in patients with malignant pleural mesothelioma
Background The attenuated, genetically engineered vaccinia virus has been shown to be a promising oncolytic virus for the treatment of patients with solid tumors, through both direct cytotoxic and immune-activating effects. Whereas systemically administered oncolytic viruses can be neutralized by pre-existing antibodies, locoregionally administered viruses can infect tumor cells and generate immune responses. We conducted a phase I clinical trial to investigate the safety, feasibility and immune activating effects of intrapleural administration of oncolytic vaccinia virus (NCT01766739). Methods Eighteen patients with malignant pleural effusion due to either malignant pleural mesothelioma or metastatic disease (non-small cell lung cancer or breast cancer) underwent intrapleural administration of the oncolytic vaccinia virus using a dose-escalating method, following drainage of malignant pleural effusion. The primary objective of this trial was to determine a recommended dose of attenuated vaccinia virus. The secondary objectives were to assess feasibility, safety and tolerability; evaluate viral presence in the tumor and serum as well as viral shedding in pleural fluid, sputum, and urine; and evaluate anti-vaccinia virus immune response. Correlative analyses were performed on body fluids, peripheral blood, and tumor specimens obtained from pre- and post-treatment timepoints. Results Treatment with attenuated vaccinia virus at the dose of 1.00E+07 plaque-forming units (PFU) to 6.00E+09 PFU was feasible and safe, with no treatment-associated mortalities or dose-limiting toxicities. Vaccinia virus was detectable in tumor cells 2-5 days post-treatment, and treatment was associated with a decrease in tumor cell density and an increase in immune cell density as assessed by a pathologist blinded to the clinical observations. An increase in both effector (CD8+, NK, cytotoxic cells) and suppressor (Tregs) immune cell populations was observed following treatment. Dendritic cell and neutrophil populations were also increased, and immune effector and immune checkpoint proteins (granzyme B, perforin, PD-1, PD-L1, and PD-L2) and cytokines (IFN-γ, TNF-α, TGFβ1 and RANTES) were upregulated. Conclusion The intrapleural administration of oncolytic vaccinia viral therapy is safe and feasible and generates regional immune response without overt systemic symptoms. Clinical trial registration https://clinicaltrials.gov/ct2/show/NCT01766739 , identifier NCT01766739.
2020-01-13 | Frequent Homozygous Deletions of Type I Interferon Genes in Pleural Mesothelioma Confer Sensitivity to Oncolytic Measles Virus
IntroductionOncolytic immunotherapy is based on the use of nonpathogenic replicative oncolytic viruses that infect and kill tumor cells exclusively. Recently, we found that the spontaneous oncolytic activity of the Schwarz strain of measles virus (MV) against human malignant pleural mesothelioma (MPM) depends on defects in the antiviral type I interferon (IFN-I) response in tumor cells.MethodsIn this study, we studied three independent human MPM bio-collections to identify the defects in the IFN-I responses in tumor cells.ResultsWe show that the most frequent defect is the homozygous deletions (HDs) of all the 14 IFN-I genes (IFN-α and IFN-β) that we found in more than half of MV-sensitive MPM cell lines. These HDs occur together with the HDs of the tumor suppressor gene CDKN2A also located in the 9p21.3 chromosome region. Therefore, the IFN-I−/− MPM cell lines develop a partial and weak IFN-I response when they are exposed to the virus compared with that of normal cells and MV-resistant MPM cell lines. This response consists of the expression of a restricted number of IFN-stimulated genes that do not depend on the presence of IFN-I. In addition, the IFN-I−/− MPM cell lines infected by MV also develop a pro-inflammatory response associated with stress of the endoplasmic reticulum.ConclusionOur study emphasizes the link between HDs of IFN-I encoding genes and the CDKN2A gene in MPM and sensitivity to MV oncolytic immunotherapy.
antibodies
2026-06-21 | Amivantamab induces immune-mediated cytotoxicity in mesothelioma via EGFR and MET engagement.
Diffuse pleural mesothelioma (DPM) is a lethal malignancy with no approved therapies directly targeting tumor cells. Based on reports that epidermal growth factor receptor (EGFR) and MET proto-oncogene (MET) are frequently expressed in DPM, we sought to systematically assess their co-expression and determine the preclinical activity of amivantamab, a bispecific antibody that targets EGFR and MET. We evaluated EGFR and MET expression in patient cohorts and cell lines using transcriptomic analysis, immunohistochemistry, and biochemical assays. The mechanistic actions of amivantamab, including receptor internalization, signaling blockade, and immune-mediated cytotoxicity, were assessed using in vitro co-culture systems with peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cells. In vivo efficacy was evaluated in mesothelioma patient-derived xenograft (PDX) models using immunodeficient mice reconstituted with human NK cells. Transcriptomic and single-cell RNA sequencing analyses of DPM patient cohorts revealed frequent co-expression of EGFR and MET, predominantly in malignant cells. Immunohistochemical analyses confirmed EGFR and MET protein expression across mesothelioma histologic subtypes. In vitro, amivantamab preferentially bound to DPM cells, inhibited ligand-induced EGFR and MET signaling, and promoted receptor internalization. Co-culture experiments demonstrated that amivantamab induced dose-dependent cytotoxicity via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC). In multiple mesothelioma PDX models, the combination of amivantamab and NK cells significantly reduced tumor growth without overt toxicity. Amivantamab demonstrates robust preclinical antitumor activity in mesothelioma primarily through innate immune-mediated cytotoxicity associated with EGFR and MET engagement. These findings support the clinical evaluation of bispecific EGFR/MET-targeting antibodies in mesothelioma.
2026-04-03 | Abstract 109: Integrative analyses of the cfDNA fragmentome and TCR repertoires capture chemo-immunotherapy response in diffuse pleural mesothelioma.
Abstract Background: Immunotherapy-containing therapies have shown promise for patients with unresectable diffuse pleural mesothelioma (DPM), yet there are no reliable strategies to monitor therapy response. By expanding the compendium of cancer-associated alterations profiled, including genome-wide fragmentation patterns, cell-free DNA (cfDNA) whole genome sequencing (WGS) enables tracking of tumor dynamics. In tandem, while understudied, T cell clone dynamics may be informative in capturing early immunotherapy response. Methods: Using 314 tumor and peripheral blood biospecimes, we analyzed serial plasma cfDNA samples (n=135) from 55 patients with unresectable DPM, who received durvalumab with platinum-based chemotherapy (NCT02899195). Following cfDNA extraction and genomic library preparation, cfDNA at baseline (C1D1), Cycle 2 Day 1 (C2D1), and Cycle 5 Day 1 (C5D1) underwent low-coverage (1-2x) whole genome sequencing. Tumor- and mutation-naive estimates of tumor fraction were derived by applying the DELFI tumor score (DELFI-TS) model, which integrates genome-wide fragmentation patterns and chromosomal arm aneuploidy. In parallel, we performed TCR Vβ CDR3 next-generation sequencing on tumor (n=43) and peripheral serial blood (n=136) samples. The TCR repertoire was characterized using clonality, TCR clonotype/cluster dynamics, and the Morisita-Horn similarity index to assess repertoire similarity across samples. Clinical outcomes were assessed by radiographic response, progression-free (PFS), and overall survival (OS). Results: Patients with distant metastasis (M1) had higher DELFI-TS levels (p=0.038). At baseline, DELFI-TS levels were numerically higher for radiographic non-responders (SD/PD) vs responders (CR/PR). Using the 92th percentile of DELFI-TS in non-cancer cfDNA control samples to determine the limit of blank, patients with detectable baseline DELFI-TS (ctDNA+) had shorter PFS and OS (log-rank p<0.001). Patients that attained a radiographic response had more clonal peripheral TCR repertoires at both baseline and on-therapy timepoints compared to non-responders (p=0.037 at C1D1; p=0.007 at C2D1; p=0.042 at C5D1). Morisita-Horn similarity between C1D1 and on-therapy was lower in non-responders than responders (p=0.019 for C1D1 vs C2D1; p=0.036 for C1D1 vs C5D1). In contrast, a more diverse intra-tumoral TCR repertoire was noted for patients with an OS of 12 or more months (p=0.018). Conclusions: Our findings provide proof-of-concept that cfDNA fragmentomic analyses can quantify pre-treatment cfDNA tumor fraction that may capture clinical outcomes with chemo-immunotherapy response for patients with DPM. Longitudinal analyses of peripheral TCR repertoires can further differentiate responding from non-responding DPM, supporting the notion that joint analyses may more accurately capture immunotherapy response. Citation Format: Jinny Huang, Jennifer Li, James R. White, Shashikant Koul, Gavin Pereira, Nisha Rao, Jennie Yao, Julie R. Brahmer, Robert B. Scharpf, Rachel Karchin, Victor E. Velculescu, Zhouxin Sun, Suresh S. Ramalingam, Patrick M. Forde, Noushin Niknafs, Valsamo (Elsa) K. Anagnostou. Integrative analyses of the cfDNA fragmentome and TCR repertoires capture chemo-immunotherapy response in diffuse pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 109.
2026-04-03 | Abstract 5547: Enhancing antibody-dependent cellular cytotoxicityin mesothelioma through concurrent EGFR and MET targeting withamivantamab
Abstract Background: Diffuse pleural mesothelioma (DPM) is a highly aggressive malignancy with limited treatment options and poor prognosis. Although immune checkpoint inhibitors have improved outcomes, particularly for non-epithelioid subtypes, there remains no approved targeted therapy for mesothelioma. EGFR and MET are receptor tyrosine kinases frequently overexpressed in DPM, suggesting susceptibility to targeted antibody therapy. Amivantamab is a bispecific EGFR/MET antibody, originally developed for EGFR-mutant lung cancer, that blocks growth signals and engaging immune mechanisms. Given the high levels of EGFR and MET expression in mesothelioma, we evaluated the therapeutic potential of amivantamab in preclinical models. Methods: EGFR and MET transcript levels in DPM were analyzed using TCGA. Eight human mesothelioma cell lines were assessed by Western blotting and flow cytometry. Amivantamab binding, internalization, and signaling inhibition were examined using flow cytometry, confocal microscopy, and ligand-stimulated phosphorylation assays. Cytotoxicity and immune-effector activity were quantified using PBMCs, NK cells, and monocytes from healthy donors, along with an ADCC reporter assay. In vivo efficacy was tested in a DPM patient-derived xenograft (PDX) model in NOD/SCID-γ (NSG) mice supplemented with human NK cells and treated with amivantamab or control IgG. Results: TCGA analysis showed frequent EGFR/MET co-expression in DPM. Mesothelioma cell lines expressed higher EGFR and MET levels compared with mesothelial cells. Amivantamab strongly bound both receptors, induced receptor internalization, and inhibited EGF- and HGF-stimulated phosphorylation of EGFR, MET, and downstream AKT/ERK signaling. Direct cytotoxicity was minimal; however, the addition of PBMCs or NK cells resulted in robust, dose-dependent tumor cell killing consistent with antibody-dependent cellular cytotoxicity (ADCC). Reporter assays demonstrated 7-11-fold Fcγ receptor activation in tumor cells compared with ∼2-fold activation in non-malignant mesothelial cells. Co-culture with monocytes revealed amivantamab-induced trogocytosis, evidenced by loss of EGFR and MET from tumor-cell membranes. In the DPM PDX model, amivantamab produced 89.1% tumor-growth inhibition (TGI) relative to controls (P < 0.0001), with no overt toxicity observed in treated mice. Conclusions: Dual EGFR/MET targeting with amivantamab produced potent antitumor effects in mesothelioma through coordinated receptor-signaling blockade, ADCC, and monocyte-mediated trogocytosis. These results support amivantamab as a promising targeted therapeutic strategy for EGFR/MET-positive DPM, particularly epithelioid subtypes that currently derive limited benefit from immunotherapy. Citation Format: Shinichiro Suzuki, Kaushal Parikh, Ezequiel Tolosa, Kuan-Li Wu, Jennifer Ayers-Ringler, Lin Yang, Katherine E. Smith, Farhad Kosari, Aaron S. Mansfield, . Enhancing antibody-dependent cellular cytotoxicityin mesothelioma through concurrent EGFR and MET targeting withamivantamab [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5547.
2025-12-30 | Determinants of Response to Immune Checkpoint Blockade in Pleural Mesothelioma: Molecular, Immunological, and Clinical Perspectives.
Diffuse pleural mesothelioma (PM) is a rare thoracic malignancy with historically limited treatment options and poor outcomes. Despite the recent breakthrough of dual immune checkpoint blockade (ICB)-notably the combination of anti-PD-1 and anti-CTLA-4 therapies-clinical responses remain variable and overall survival gains modest. Consequently, there is an urgent need for multidimensional biomarkers and adaptive trial designs to unravel the complexity of PM immune biology. This review provides a comprehensive overview of current evidence on how histological subtypes (epithelioid vs. non-epithelioid) influence ICB efficacy, highlighting distinct genetic landscapes (e.g., BAP1, CDKN2A, NF2 mutations) and tumor microenvironment (TME) features, including immune infiltration patterns and PD-L1 or VISTA expression, that underlie differential responses. We further examine intrinsic tumor factors-such as mutational burden and checkpoint ligand expression-and extrinsic determinants, including immune cell composition, stromal architecture, patient immune status, and microbiota, as modulators of immunotherapy outcomes. We also discuss the rationale behind emerging strategies designed to enhance ICB efficacy, currently under clinical evaluation. These include combination regimens with chemotherapy, radiotherapy, surgery, epigenetic modulators, anti-angiogenic agents, and novel immunotherapies such as next-generation checkpoint inhibitors (LAG-3, VISTA), immune-suppressive cell-targeting agents, vaccines, cell-based therapies, and oncolytic viruses. Collectively, these advancements underscore the importance of integrating histological classification with molecular and microenvironmental profiling to refine patient selection and guide the development of combination strategies aimed at transforming "cold" mesotheliomas into "hot," immune-responsive tumors, thereby enhancing the efficacy of ICB.
2025-11-01 | 510 Dynamic tumor and immune response to neoadjuvant nivolumab with chemotherapy in diffuse pleural mesothelioma
Background Diffuse pleural mesothelioma (DPM) is an aggressive malignancy with poor outcomes even in potentially resectable disease. With an evolving understanding of the role of pleurectomy/decortication (P/D) in patients with resectable disease, the need to optimize and improve upfront therapies is more urgent. Here, we report on transcriptional and spatial correlates of progression free survival from this single institution prospective pilot study of nivolumab with platinum (cisplatin/carboplatin) and pemetrexed prior to P/D (2 cycles) for patients with resectable DPM ( NCT04162015).Methods To comprehensively assess tumor and immune microenvironment changes after immunotherapy with chemotherapy in DPM, single cell RNAseq was performed on 20 resection specimens from 16 patients with available material, including three patients with matched pre/post resection specimens. In addition, peripheral blood mononuclear cell (PBMC) from pre/post treatment, whole exome sequencing, and spatial analyses were studied to comprehensively understand treatment resistance to immunotherapy with chemotherapy in this rare tumor type. Here we report on the transcriptional and spatial tumor microenvironment changes that correlate with response after treatment from generating the largest cohort of DPM resection specimens analyzed by single-cell RNAseq.Results 22 patients received neoadjuvant chemo-immunotherapy and 19 underwent attempted P/D (2 progressed and 1 declined surgery) within 30 days of the planned resection date. Of the 19 patients that went for P/D, the median OS from the start of neoadjuvant therapy was 34mos with a progression free survival (PFS) of 14mos (median follow-up: 32mos). We discover that after two cycles of chemotherapy with nivolumab long-term responders (PFS>12 months) have a tumor microenvironment enriched by lymphocytes (CD4+ and CD8+ T cells as well as NK cells) while short-term responders had an abundance of myeloid cells. Short term responders had a clear enrichment of an IFN-responsive signature in tumor cells. Further analysis revealed that enrichment of clonally expanded CD8+ tumor reactive T-cells with exhaustion features, GZMK+ effector memory CD8+ T cells, and a shift from monocytes to APOE+ macrophages were features of the tumor immune compartment in long term responders. Moreover, we discover that DPM cells exist on a phenotypic-continuum between mesothelial-like and fibroblast-like states. Leveraging spatial transcriptomics, we find fibroblast-like tumor cells occupy spatially distinct tumor regions characterized by poor immune infiltrate and high TGFβ-signatures.Conclusions This in-depth characterization of the largest cohort of DPM resection specimens analyzed at a single cell level after neoadjuvant treatment provides foundational insights to characterize DPM responders to chemo-IO and support future therapeutic development.
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2026-04-03 | Abstract 2052: miR-342-5p: A promising tumor suppressor in diffuse pleural mesothelioma.
Abstract Diffuse pleural mesothelioma (DPM) is an incurable, aggressive neoplasm with limited therapies. Moving beyond conventional approaches, we posit that microRNAs (miRNA), short, non-coding RNA that coherently regulate gene expression, can uniquely disrupt the molecular networks involved in DPM. In this study, we identified miR-342-5p as a novel DPM-associated miRNA. We used a human miRNA mimic library to screen for miRNAs with antiproliferative effects on a panel of DPM cell lines. Among the most potent candidates was miR-342-5p. We profiled the downregulation of miR-342-5p in DPM patient specimens compared to normal pleura (Normal=22, Tumor=50). TCGA-MESO analysis revealed that miR-342-5p downregulation is significantly associated with poor survival outcomes. Our results demonstrated that the re-expression of miR-342-5p significantly impaired DPM cell viability, reduced 2D colony foci formation, and inhibited anchorage-independent cell growth in soft-agar and sphere assays. Additionally, Annexin-V assays showed a significant increase in early and late apoptotic cells in miR-342-5p transfected DPM cells compared to controls. Furthermore, we confirmed the induction of apoptosis in miR-342-5p-treated DPM cells through PARP cleavage and the activation of caspase-3/7. Importantly, no significant biological effects were observed when normal human mesothelial cells (NP1 line) were treated with miR-342-5p. Next, we performed a Biotin-miRNA (Bi-miR) pull-down assay, a direct binding assay in which a biotin-tagged miR-342-5p probe captures its associated mRNA transcripts in a pooled lysate. Then, RNA-seq analysis is conducted to identify direct target genes associated with apoptosis and cell death pathways in DPM. We identified the top transcripts targeted by miR-342-5p that are also involved in its tumor-suppressive activity in DPM. Overall, our findings highlight the tumor suppressive effects and therapeutic potential of miR-342-5p for DPM treatment. Citation Format: So-Hyun Yoon, Anand Singh, Nathanael Pruett, Vivek Singh, Smrity Sahu, Yelixza Avila, Chuong Hoang. miR-342-5p: A promising tumor suppressor in diffuse pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2052.
2023-08-07 | Coengineering specificity, safety, and function into T cells for cancer immunotherapy
Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma. Moreover, for a variety of reasons, relative limited efficacy has been demonstrated for ACT of non-hematological solid tumors. Indeed, in addition to pre-infusion challenges including lymphocyte collection and manufacturing, ACT failure can be attributed to several biological processes post-transfer including, (i) inefficient tumor trafficking, infiltration, expansion and retention, (ii) chronic antigen exposure coupled with insufficient costimulation resulting in T-cell exhaustion, (iii) a range of barriers in the tumor microenvironment (TME) mediated by both tumor cells and suppressive immune infiltrate, (iv) tumor antigen heterogeneity and loss, or down-regulation of antigen presentation machinery, (v) gain of tumor intrinsic mechanisms of resistance such as to apoptosis, and (vi) various forms of toxicity and other adverse events in patients. Affinity-optimized TCRs can improve T-cell function and innovative CAR designs as well as gene-modification strategies can be used to coengineer specificity, safety, and function into T cells. Coengineering strategies can be designed not only to directly support the transferred T cells, but also to block suppressive barriers in the TME and harness endogenous innate and adaptive immunity. Here, we review a selection of the remarkable T-cell coengineering strategies, including of tools, receptors, and gene-cargo, that have been developed in recent years to augment tumor control by ACT, more and more of which are advancing to the clinic.
2023-03-31 | Data from Enhanced Antitumor Therapy by Inhibition of p21<sup>waf1</sup> in Human Malignant Mesothelioma
<div>Abstract<p><b>Purpose:</b> The p21 cyclin-dependent kinase inhibitor was frequently expressed in human malignant pleural mesothelioma (MPM) tissues as well as cell lines. Recent data indicate that p21 keeps tumor cells alive after DNA damage, favoring a survival advantage. In this study, we assessed the possibility of p21 suppression as a therapeutic target for MPM.</p><p><b>Experimental Design:</b> We established two different MPM-derived (from H28 and H2052 cells) subclones using vector-based short hairpin RNA (shRNA). Then, chemosensitivity against low doses of antineoplastic DNA-damaging agents was investigated by colony formation assays, and furthermore, the type of cell response induced by these drugs was analyzed. To examine the effect of p21 shRNA on chemosensitivity <i>in vivo</i>, tumor formation assays in nude mice were done.</p><p><b>Results:</b> In colony formation assay, the IC<sub>50</sub> of doxorubicin was 33 ± 3.0 nmol/L in p21 shRNA-transfected cells with respect to 125 ± 10 nmol/L of control vector–transfected cells. This enhancement of growth inhibition was achieved by converting a senescence-like growth arrest to apoptosis in response to doxorubicin, etoposide, and CPT11. In the <i>in vivo</i> assays, CPT11 and loss-of-expression of p21 in combination led to considerable suppression of tumor growth associated with a substantially enhanced apoptotic response, whereas CPT11 alone was ineffective at inducing these responses.</p><p><b>Conclusions:</b> These results indicated that p21 might play an important role in chemosensitivity to anticancer agents, and the suppression of its expression might be a potential therapeutic target for MPM.</p></div>
2022-11-26 | The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Drug Target Evaluation
Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors BAP1, NF2 and P16 may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses. Ten cell lines, representing the spectrum of histological subtypes and tumour suppressor status, were dual labelled for fluorescence/bioluminescence imaging and implanted on the CAM at E7. Bioluminescence was used to assess viability of primary tumours, which were excised at E14 for immunohistological staining or real-time PCR. All MPM cell lines engrafted efficiently forming vascularised nodules, however their size, morphology and interaction with chick cells varied. MPM phenotypes including local invasion, fibroblast recruitment, tumour angiogenesis and vascular remodelling were evident. Bioluminescence imaging could be used to reliably estimate tumour burden pre- and post-treatment, correlating with tumour weight and Ki-67 staining. In conclusion, MPM-CAM models recapitulate important features of the disease and are suitable to assess drug targets using a broad range of MPM cell lines that allow histological or genetic stratification. They are amenable to multi-modal imaging, potentially offering a time and cost-efficient, 3Rs-compliant alternative to rodent xenograft models to prioritise candidate compounds from in vitro studies.
2022-09-20 | The Chick Embryo Xenograft Model for Malignant Pleural Mesothelioma: A Cost and Time Efficient 3Rs Model for Target and Compound Evaluation
Malignant pleural mesothelioma (MPM) has limited treatment options and poor prognosis. Frequent inactivation of the tumour suppressors BAP1, NF2 and P16 may differentially sensitise tumours to treatments. We have established chick chorioallantoic membrane (CAM) xenograft models of low-passage MPM cell lines and protocols for evaluating drug responses. Ten cell lines, representing the spectrum of histological subtypes and tumour suppressor status, were dual labelled for fluorescence/bioluminescence imaging and implanted on the CAM at E7. Bioluminescence was used to assess viability of primary tumours, which were excised at E14 for immunohistological staining or real-time PCR. All MPM cell lines engrafted efficiently forming vascularised nodules, however their size, morphology and interaction with chick cells varied. MPM phenotypes including local invasion, fibroblast recruitment, tumour angiogenesis and vascular remodelling were evident. Bioluminescence imaging could be used to reliably estimate tumour burden pre- and post-treatment, correlating with tumour weight and Ki-67 staining. In conclusion, MPM-CAM models recapitulate important features of the disease and are suitable to assess therapies using a broad range of MPM cell lines that allow histological or genetic stratification. They are amenable to multi-modal imaging, offering a time and cost-efficient, 3Rs-compliant alternative to rodent xenograft models to prioritise candidate compounds from in vitro studies.
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