small molecules

2026-08-10 | Complications and adverse events of cytoreductive surgery in malignant peritoneal lesions

Cytoreductive surgery combined with intraoperative intraperitoneal chemotherapy is the treatment of choice for patients with malignant peritoneal lesions. Objective. To evaluate the validity and safety of surgical interventions in patients with primary and disseminated peritoneal lesions by analyzing the frequency and severity of intra- and postoperative complications. Material and methods. The Abdominal Department of the P.A. Hertzen Moscow Oncology Research Institute has accumulated experience in performing 168 cytoreductive surgeries with various intraoperative antitumor methods in patients with peritoneal carcinomatosis. Among them, 125 surgeries were for pseudomyxoma peritonei, 25 for mesothelioma, and in 18 cases, the indication for intervention was peritoneal metastases of colorectal cancer. Results. Complications and serious adverse events were identified in 31 (18.4%) patients. Grade III—IV complications occurred in 6.5% of patients. Postoperative mortality was 2.9%, which does not exceed the rate for major surgical interventions such as pancreaticoduodenectomy, simultaneous esophageal resection and reconstruction, and extended hemihepatectomy. Conclusion. Cytoreductive surgery for malignant peritoneal lesions is a sufficiently safe and effective treatment method for this category of patients.

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2026-07-21 | Epidemiological and Prognostic Differences in Malignant Mesothelioma Between Eastern China and SEER Database.

Eastern China malignant mesothelioma (MM) presents distinct features-younger age, female predominance, and moremalignant peritoneal mesothelioma (MPeM)-contrasting with the Western profile of older males with malignant pleural mesothelioma (MPM). Robust survival data for this population are still unavailable. This retrospective study included 253 MM patients from Zhejiang Cancer Hospital (2010-2024; 222 from Zhejiang Province, ZJ cohort) to update regional epidemiology and compare survival with the Surveillance, Epidemiology, and End Results program (SEER). The ZJ cohort exhibited a younger median age at diagnosis (58 vs. 74 years), a higher proportion of females (62% vs. 24%), and a higher prevalence of MPeM (54% vs. 11%) relative to the SEER cohort. Overall survival (OS) was significantly prolonged in the ZJ cohort (median OS: 22 vs. 10 months), with survival benefits consistently observed across sex, age, and MPM subgroups. Multivariate Cox analysis revealed age as the only consistent independent prognostic factor in both ZJ and SEER cohorts. Following propensity score matching to minimize confounding, the ZJ cohort maintained a significantly longer survival in MPM but exhibited worse outcome in MPeM relative to SEER. Collectively, this study not only updated epidemiologic features for MM in Eastern China but also reported the unique survival patterns, uncovering inter-population heterogeneity. These findings emphasize the value of region-specific prognostic evidence and the limitations of directly applying Western data to Asian populations.

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2026-06-30 | Navigating the Foggy Landscape of Epithelioid Peritoneal Mesothelioma: A Proposed Standardized Institutional Algorithm for Multimodal Management

Purpose: Diffuse malignant peritoneal mesothelioma is a rare disease requiring management in specialized referral centers. We report our institutional experience with epithelioid diffuse malignant peritoneal mesothelioma, focusing on a standardized treatment algorithm and on pre-operative cisplatin–pemetrexed as a bridge to cytoreductive surgery and HIPEC. Methods: Consecutive patients treated between 2016 and 2024 were retrospectively reviewed. Treatment allocation was based on diagnostic laparoscopy, PCI assessment, and multidisciplinary evaluation. Patients with technically resectable disease underwent upfront CRS–HIPEC, whereas borderline or unresectable patients received cisplatin–pemetrexed followed by systematic reassessment. Results: Forty-three patients were included; 19 underwent CRS–HIPEC, including 8 after pre-operative chemotherapy, and 24 received medical management alone. Curative-intent cytoreduction (CC-0/1) was achieved in all operated patients, with no 30-day mortality. No statistically significant difference in overall survival was detected between upfront and conversion surgery patients in this small cohort. Higher PCI and Ki-67 were independently associated with worse overall survival. Conclusions: A structured multidisciplinary pathway may support tailored treatment selection in epithelioid diffuse malignant peritoneal mesothelioma. In selected responders, cisplatin–pemetrexed may act as a bridge to surgery, although larger studies are required to validate this strategy.

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2026-05-22 | FASN for diffuse malignant peritoneal mesothelioma: a prognostic biomarker after CRS+HIPEC and a therapeutic target.

Diffuse malignant peritoneal mesothelioma (DMPM) is a rare and aggressive malignancy with limited therapeutic options and poor clinical outcomes. While metabolic reprogramming, including altered lipid metabolism, is a recognized hallmark of cancer, its contribution to DMPM progression and treatment response remains poorly understood. Gene expression profiling was performed on tumor samples from 45 DMPM patients treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS+HIPEC), comparing patients who developed recurrence within 30 months (N = 13) to those with later relapse or no recurrence (N = 32). Candidate prognostic markers were validated by immunohistochemistry in a cohort of 80 DMPM patients treated with CRS+HIPEC. Associations with progression-free survival (PFS) and overall survival (OS) were assessed using univariate and multivariate Cox regression analyses. To evaluate therapeutic potential, selective (cerulenin, C75) and non-selective (orlistat) fatty acid synthase (FASN) inhibitors were tested in patient-derived DMPM cell lines. Effects on cell proliferation, cell cycle progression, and apoptosis were assessed. Combination treatments with selinexor (XPO1/CRM1 inhibitor) or IAG-933 (inhibitor of FASN-derived palmitoyl-CoA activity) were also evaluated. Fatty acid synthase (FASN) was significantly upregulated in tumors from patients with early recurrence. High FASN protein expression was associated with reduced PFS (HR = 1.93; p = 0.01) and OS (HR = 1.85; p = 0.02). Multivariate analysis confirmed FASN as an independent predictor of both PFS (HR = 2.24; p = 0.005) and OS (HR = 2.24; p = 0.014). In vitro, FASN inhibition significantly reduced DMPM cell growth, disrupted cell cycle progression, and induced apoptosis, with C75 showing the strongest effects. Combination treatment with FASN inhibitors and selinexor or IAG-933 resulted in enhanced growth inhibition and apoptosis compared with single-agent treatments. FASN represents a novel independent prognostic biomarker in DMPM patients undergoing CRS+HIPEC and a promising therapeutic target. Given the limited treatment options for DMPM, combination strategies incorporating FASN inhibitors with selinexor or TEAD-pathway-targeting agents, supported by existing clinical trial data, may offer a rapidly translatable therapeutic approach.

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2026-05-12 | PIPAC for Malignant Peritoneal Mesothelioma: Current Insights and Future Directions.

Malignant peritoneal mesothelioma (MPM) is a rare and aggressive tumour with poor prognosis, often diagnosed late due to nonspecific symptoms. Current standard treatment involves systemic chemotherapy and cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC), but this approach is limited to selected patients. Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) has emerged as a novel technique improving drug delivery and penetration in the peritoneal cavity. This narrative review evaluates the role of PIPAC in the treatment of MPM, analysing data from clinical studies on its feasibility, safety, and efficacy. Evidence suggests that PIPAC is a well-tolerated procedure, with a manageable safety profile and potential to improve survival and tumour response in patients with unresectable or recurrent disease. Limitations in current studies include small cohorts and heterogeneous patient populations, underscoring the need for further research. PIPAC represents a promising therapeutic option, offering enhanced intraperitoneal chemotherapy (IPC) delivery with minimal systemic toxicity. Future investigations should focus on optimizing treatment protocols and evaluating long-term benefits to better define PIPAC's role in clinical practice.

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proteins

2025-04-21 | Dynamic evolution of NK cells and immune remodeling mediated by CRS+HIPEC: prognostic mechanisms and therapeutic implications for malignant peritoneal mesothelioma

Background: Malignant peritoneal mesothelioma (MPM) is a highly aggressive peritoneal malignancy with a significant recurrence rate following cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). Thus, there is an urgent need to investigate novel therapeutic strategies for MPM. Natural killer (NK) cells exhibit rapid responsiveness in anti-tumor immunity; however, NK cells' dynamic evolution and clinical significance in MPM remain unclear. Methods: This study retrospectively enrolled 80 newly diagnosed MPM patients (preoperative group) and 64 patients who underwent CRS+HIPEC (postoperative group). The frequency of NK cells (CD3-CD56dimCD16+) in peripheral blood was quantified using flow cytometry. Univariate and multivariate regression analyses were performed to evaluate the association between NK cell counts and clinicopathological characteristics, intraoperative events, and prognosis. A multivariate prediction model for NK cell recovery was established. Results: Preoperative NK cell reduction was observed in 41 patients (51.3%), and this phenomenon was significantly associated with preoperative thrombosis (P = 0.023), a high intraoperative plasma infusion volume (P = 0.004), prolonged hospital stay (P = 0.023), decreased total lymphocyte count (P = 0.011), and an elevated CD4+/CD8+T cell ratio (P = 0.018). The median NK cell count increased significantly to 278 cells/μL postoperatively. Postoperative NK cell reduction occurred in 20 cases (31.3%), which was independently correlated with lower Karnofsky performance scale (KPS) scores (P = 0.048), and higher expression levels of interleukins IL-4 (P = 0.020), IL-5 (P = 0.007), IL-6 (P = 0.016), and IL-8 (P = 0.018). Elevated levels of IL-2 (P = 0.019) and IL-4 (P = 0.007) were identified as independent factors contributing to NK cell depletion following surgery. Survival analysis revealed that a high perioperative stress score (PSS) (P = 0.015), lymph node metastasis (P = 0.015), intraoperative blood loss (P = 0.013), low preoperative CD8⁺T cell levels (P = 0.001), and low postoperative IL-17 expression levels (P = 0.013) were independent adverse predictors of overall survival (OS). Patients with higher preoperative NK cell levels exhibited a tendency toward longer OS. Furthermore, the dynamic NK recovery model demonstrated that baseline NK cell levels (P < 0.001), peritoneal cancer index (PCI) (P < 0.001), CD8⁺T cell status (P < 0.001), and postoperative recovery time (P < 0.001) all influenced the immune remodeling process. Conclusions: This study represents the first systematic investigation into the spatiotemporal dynamic characteristics of NK cells in MPM patients. More than half of MPM patients experienced preoperative NK cell depletion, which CRS+HIPEC could effectively reverse. The NK cell count may serve as a dynamic biomarker for tumor burden and immunosuppressive microenvironment assessment, with its preoperative elevation potentially improving prognosis. Targeting the IL-2/IL-4 pathway alone or in combination with CD8⁺ T cells may offer a novel strategy for MPM immunotherapy.

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2023-06-22 | The amino-acid stress sensing eIF2α kinase GCN2 is a survival biomarker for malignant mesothelioma

Abstract Background Malignant mesothelioma is a tumour that is strongly associated with a history of asbestos exposure, and which derives from mesothelial cells that line the serous cavities of the body. The tumour most commonly arises in the pleural cavity, but can also arise in the pericardium, peritoneum, and tunica vaginalis. At present the lesion has a very poor prognosis and is an incurable form of cancer with median survival times of up to 19 months being quoted for some histological subtypes. A large proportion of mesotheliomas have been shown to be arginine auxotrophic, leading to new research for therapeutics which might exploit this potential vulnerability. Methods We measured the levels of General Control Non-derepressible 2 (GCN2) protein in malignant mesothelioma tumour samples and determined whether these levels correlate with clinical outcomes. Results We observed that the expression levels of GCN2 correlated with patient survival and was an independent prognostic variable in pairwise comparisons with all available clinical data. Conclusion These findings suggest that GCN2 levels provides prognostic information and may allow for stratification of care pathways. It may suggest that targeting GCN2 is a viable strategy for mesothelioma therapy development.

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2023-04-01 | Data from Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors

<div>AbstractPurpose:<p>IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure.</p>Experimental Design:<p>We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis.</p>Results:<p>IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69⁺CD44⁺ and CD69⁻CD44⁺CD62L⁻ T cells, reduction of CD86⁻PD-L1⁻ M2-like macrophages, and a corresponding increase in CD86⁺PD-L1⁺ M1-like macrophages and MHC-II⁺ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use.</p>Conclusions:<p>IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-2626" target="_blank">See related commentary by Palanki et al., p. 5010</a></i></p></div>

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2022-09-12 | Activation of Adaptive and Innate Immune Cells via Localized IL2 Cytokine Factories Eradicates Mesothelioma Tumors

Abstract Purpose: IL2 immunotherapy has the potential to elicit immune-mediated tumor lysis via activation of effector immune cells, but clinical utility is limited due to pharmacokinetic challenges as well as vascular leak syndrome and other life-threatening toxicities experienced by patients. We developed a safe and clinically translatable localized IL2 delivery system to boost the potency of therapy while minimizing systemic cytokine exposure. Experimental Design: We evaluated the therapeutic efficacy of IL2 cytokine factories in a mouse model of malignant mesothelioma. Changes in immune populations were analyzed using time-of-flight mass cytometry (CyTOF), and the safety and translatability of the platform were evaluated using complete blood counts and serum chemistry analysis. Results: IL2 cytokine factories enabled 150× higher IL2 concentrations in the local compartment with limited leakage into the systemic circulation. AB1 tumor burden was reduced by 80% after 1 week of monotherapy treatment, and 7 of 7 of animals exhibited tumor eradication without recurrence when IL2 cytokine factories were combined with anti–programmed cell death protein 1 (aPD1). Furthermore, CyTOF analysis showed an increase in CD69+CD44+ and CD69−CD44+CD62L− T cells, reduction of CD86−PD-L1− M2-like macrophages, and a corresponding increase in CD86+PD-L1+ M1-like macrophages and MHC-II+ dendritic cells after treatment. Finally, blood chemistry ranges in rodents demonstrated the safety of cytokine factory treatment and reinforced its potential for clinical use. Conclusions: IL2 cytokine factories led to the eradication of aggressive mouse malignant mesothelioma tumors and protection from tumor recurrence, and increased the therapeutic efficacy of aPD1 checkpoint therapy. This study provides support for the clinical evaluation of this IL2-based delivery system. See related commentary by Palanki et al., p. 5010

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2022-02-08 | Use of an antagonist of HMGB1 in mice affected by malignant mesothelioma: a preliminary ultrasound and optical imaging study

Abstract Background Malignant mesothelioma (MM) is an aggressive tumor, with a poor prognosis, usually unresectable due to late diagnosis, mainly treated with chemotherapy. BoxA, a truncated form of “high mobility group box 1” (HMGB1), acting as an HMGB1 antagonist, might exert a defensive action against MM. We investigated the potential of BoxA for MM treatment using experimental 40-MHz ultrasound and optical imaging (OI) in a murine model. Methods Murine MM cells infected with a lentiviral vector expressing the luciferase gene were injected into the peritoneum of 14 BALB/c mice (7 × 10 4 AB1-B/c-LUC cells). These mice were randomized to treatment with BoxA ( n = 7) or phosphate-buffered saline (controls, n = 7). The experiment was repeated with 40 mice divided into two groups ( n = 20 + 20) and treated as above to confirm the result and achieve greater statistical power. Tumor presence was investigated by experimental ultrasound and OI; suspected peritoneal masses underwent histopathology and immunohistochemistry examination. Results In the first experiment, none of the 7 controls survived beyond day 27, whereas 4/7 BoxA-treated mice (57.1%) survived up to day 70. In the second experiment, 6/20 controls (30.0%) and 16/20 BoxA-treated mice (80.0%) were still alive at day 34 ( p = 0.004). In both experiments, histology confirmed the malignant nature of masses detected using experimental ultrasound and OI. Conclusion In our preclinical experience on a murine model, BoxA seems to exert a protective role toward MM. Both experimental ultrasound and OI proved to be reliable techniques for detecting MM peritoneal masses.

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antibodies

2026-09-18 | Case Report: Iparomlimab and Tuvonralimab-based therapy for epithelioid malignant peritoneal mesothelioma: a three-case series.

Epithelioid malignant peritoneal mesothelioma (EMPM) is a rare and aggressive malignancy of serosal origin. Cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy is generally reserved for carefully selected patients in whom adequate cytoreduction appears feasible, while evidence supporting systemic immunotherapy remains limited for patients with unresectable disease or those unable to tolerate intensive treatment. Iparomlimab and tuvonralimab (QL1706) is a fixed-ratio anti-PD-1/anti-CTLA-4 MabPair formulation that has shown preliminary antitumor activity in several advanced solid tumors, but clinical experience in EMPM remains scarce. We retrospectively describe three patients with EMPM diagnosed through integrated clinicopathologic assessment who received QL1706 either as monotherapy or in combination with an antiangiogenic agent. Treatment response was assessed by the treating team on serial computed tomography (CT) using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) as the evaluation framework. Case 1 was a 53-year-old woman with a programmed death-ligand 1 (PD-L1) combined positive score (CPS) of 10. Diffuse peritoneal disease persisted after surgery and three sessions of postoperative catheter-based hyperthermic intraperitoneal chemotherapy. QL1706 plus bevacizumab subsequently produced stable disease with symptomatic improvement for approximately 7 months. Case 2 was an 89-year-old man with a PD-L1 CPS of 0 who was considered unsuitable for surgery or intensive chemotherapy. QL1706 plus dose-reduced lenvatinib achieved a partial response that remained ongoing for more than 10 months. Case 3 was a 70-year-old man with a PD-L1 CPS of 55 and pre-existing nephrotic syndrome. QL1706 monotherapy induced a rapid partial response, but treatment was discontinued because of worsening proteinuria and edema; the disease subsequently progressed, with a new intracranial lesion radiologically suspicious for metastasis. QL1706-based therapy achieved disease control in all three patients with EMPM who had limited conventional treatment options, including a durable response in an elderly patient with PD-L1-negative disease and rapid tumor regression with QL1706 monotherapy. The contrasting clinical courses suggest that overall benefit depends not only on tumor sensitivity but also on the accompanying treatment strategy and baseline organ function.

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2026-02-19 | Analysis on the efficacy and safety of chemotherapy combined with or without bevacizumab after CRS+HIPEC in patients with malignant peritoneal mesothelioma: a single-center retrospective study.

To investigate the efficacy and safety of pemetrexed/platinum-based chemotherapy combined with or without bevacizumab after cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of patients with malignant peritoneal mesothelioma (MPM). A retrospective non-randomized study was performed on 205 MPM patients treated with CRS+HIPEC at our institution. A total of 97 eligible patients were analyzed: 58 patients who received postoperative chemotherapy combined with bevacizumab (C&B) and 39 patients who received chemotherapy alone (C) were divided into a study group and a control group, respectively. The patients were also divided into the bevacizumab-exposed subgroup and the bevacizumab-unexposed subgroup based on whether they had a history of bevacizumab infusion. Clinicopathological data and follow-up information were statistically analyzed. Independent prognostic factors were identified via survival analysis, and the safety of combination therapy was assessed via adverse event analysis. As of the follow-up cutoff date of July 1, 2025, in both the subgroups with and without a history of bevacizumab infusion, there was no statistically significant difference between the control and study groups in baseline pathological characteristic parameters (p > 0.05). Survival analysis revealed that in the subgroup of patients with a history of bevacizumab infusion, the difference in median overall survival (mOS) between the control and study groups was statistically significant (31.9 months vs. NR; p = 0.031), and the difference in median disease-free survival (mDFS) between the control and study groups was statistically significant (12.5 months vs. NR; p = 0.001); in the subgroup of patients without a history of bevacizumab infusion, the difference in mOS between the control and study groups was also statistically significant (20.5 months vs. NR; p = 0.001), and the difference in mDFS between the control and study groups was statistically significant (13.2 vs. 36.2 months; p = 0.001). The Cox regression model found that postoperative C&B was an independent prognostic factor (p = 0.009, HR = 0.081, 95% CI: 0.012-0.526) in the subgroup with a history of bevacizumab infusion, and the Ki-67 index (p = 0.043, HR = 2.563, 95% CI: 1.029-6.386) and postoperative C&B were independent prognostic factors (p = 0.01, HR = 0.086, 95% CI: 0.032-0.232) in the subgroup with no bevacizumab treatment history. A total of 101 cases of grade 1~2 adverse events in the study group were revealed via adverse event analysis, with common events including nausea/vomiting, fatigue, leukopenia/neutropenia, thrombocytopenia, anemia, abnormal liver function, hypertension, and proteinuria. There were four cases with grade 3 adverse events, mainly leukopenia/neutropenia, hypertension, and proteinuria. In the control group, there were 84 cases of grade 1~2 adverse events, and three cases of grade 3 adverse events were observed. Our exploratory findings suggest that bevacizumab combined with pemetrexed/platinum-based chemotherapy may be a therapeutic option for MPM patients after CRS+HIPEC; however, a prospective, randomized controlled clinical study is needed to validate our findings.

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2025-11-10 | Real-world immunotherapy outcomes in unresectable peritoneal mesothelioma: A French experience.

Peritoneal mesothelioma is a rare disease treated with curative approach- cytoreductive surgery and hyperthermic intraperitoneal chemotherapy -when resectable.In case of inoperable disease or extra-peritoneal involvement, the standard of care is based primarily on systemic chemotherapy. Platinum-based chemotherapy is used in the first-line setting, but no standard exists for subsequent lines.Peritoneal mesothelioma harbors a pro-inflammatory tumor microenvironment, making it potentially sensitive to immune checkpoint inhibitors (ICIs). We included inoperable patients with peritoneal mesothelioma treated between 2017 and 2024 at two institutions in France, using ICIs-based treatments (immunotherapy with or without anti-angiogenic agents).The primary endpoints were progression-free survival (PFS) and overall survival (OS). A total of 22 patients with peritoneal mesothelioma were included.The median age at diagnosis was 57 years (IQR: 50-66);the majority had epithelioid histology (n = 17; 77 %).After a median follow-up of 13.76 months (95 % CI: 6.40-22.49),median Progression free survival(PFS) was 10.22 months (95 % CI: 4.82-15.87),median Overall Survival(OS) was 16.8 months (95 % CI: 6.46-37.73) No significant differences in PFS (p = 0.73) or OS (p = 0.16) were observed between BAP1-positive and BAP1-negative tumors.Among evaluable patients (n = 13, 62 %), the objective response rate was 30 % (95 % CI: 22 %-50 %).The disease control rate at 6 and 12 months for the entire cohort was:55 % (95 % CI: 33 %-74.5 %) at 6 months and 41 % (95 % CI: 21.9 %-63.04 %) at 12 months.Grade 3 toxicity occurred in 3 patients; no grade 4 toxicity was reported. The benefit of ICI-based treatment was confirmed in this European real-world cohort and should be considered as a treatment option in this rare setting.

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2025-11-09 | Use of Neoadjuvant Immunotherapy in Malignant Peritoneal Mesothelioma as a Bridge to Surgical Intervention: A Case Report.

BACKGROUND Malignant peritoneal mesothelioma (MPM) is a rare subtype of malignant mesothelioma (MM) that arises from mesothelial/serosal surfaces of the peritoneal lining and carries a poor prognosis. Given the rarity of this disease, many expert groups such as the Peritoneal Surface Oncology Group International (PSOGI) and the National Comprehensive Cancer Network (NCCN) have developed recommendations to guide the optimal treatment for MPM. Currently, the standard of care for resectable MPM is a combination of cytoreductive surgery (CRS) followed by hyperthermic intraperitoneal chemotherapy (HIPEC). There are no clear guidelines for treatment of inoperable malignant mesothelioma, but several studies have demonstrated a benefit of incorporating immunotherapy in the treatment plan. CASE REPORT We present a case of a 63-year-old woman who sought medical attention for several months of persistent vague abdominal discomfort, weight loss, and night sweats. Laboratory workup and diagnostic imaging led to the diagnosis of borderline/unresectable MPM. A multidisciplinary tumor board discussion based on the published literature and guidelines on malignant mesothelioma (MM) was undertaken, and the decision was made to treat the patient with nivolumab-ipilimumab in the perioperative period. The patient had a positive clinical response allowing for subsequent CRS and HIPEC. She remains disease free 30 months following her surgery, with the intention to continue the immunotherapy. CONCLUSIONS This case report contributes to the current literature demonstrating a potential role for perioperative immunotherapy in the treatment of aggressive subtype or borderline resectable/unresectable MPM and a bridge to consolidative CRS/HIPEC.

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2025-09-02 | Efficacy of postoperative immunotherapy on MPM patients after CRS + HIPEC: A single-center retrospective study based on propensity score matching.

To investigate the efficacy of postoperative immunotherapy in patients with malignant peritoneal mesothelioma (MPM) after cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). The clinical data of 160 MPM patients who underwent CRS + HIPEC at our center from April 2015 to February 2024 were retrospectively analyzed. All patients received postoperative chemotherapy and were divided into the Chemo-only group and the Immunotherapy group according to whether they received postoperative immunotherapy or not. Propensity score matching (PSM) was used to match baseline characteristics. The median overall survival (OS) was compared between the two groups. The Cox regression model was used to determine the independent prognostic factors, and subgroup analysis was performed to calculate the interaction. After matching, a total of 70 patients were included for final analysis, consisting of 35 patients each in the Chemo-only and Immunotherapy groups. Survival analysis showed that the median OS was significantly longer in the Immunotherapy group than the Chemo-only group (not-reached [NR] vs. 28.4 months) (p = 0.001). Univariate and multivariate Cox analyses indicated that postoperative immunotherapy was an independent protective factor for OS. Furthermore, subgroup analysis suggested that the results were generally robust, with no significant interactions. The median OS of sintilizumab was probably superior to camrelizumab (NR vs. 40.0 months, p = 0.052) and significantly longer than other immunotherapy regimens (pembrolizumab, cardunnilumab, nivolumab+ipilimumab) (NR vs. 26.7 months, p = 0.008). Postoperative immunotherapy, when compared to postoperative chemotherapy alone, could enhance the survival of MPM patients following CRS + HIPEC.

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gene therapies

2024-01-15 | Efficacy of Different Oncolytic Vaccinia Virus Strains for the Treatment of Murine Peritoneal Mesothelioma

Effective treatment options for peritoneal surface malignancies (PSMs) are scarce. Oncolytic virotherapy with recombinant vaccinia viruses might constitute a novel treatment option for PSM. We aimed to identify the most effective oncolytic vaccinia virus strain in two murine mesothelioma cell lines and the oncolytic potential in a murine model of peritoneal mesothelioma. Cell lines AB12 and AC29 were infected in vitro with vaccinia virus strains Lister (GLV-1h254), Western Reserve (GLV-0b347), and Copenhagen (GLV-4h463). The virus strain GLV-0b347 was shown most effective in vitro and was further investigated by intraperitoneal (i.p.) application to AB12 and AC29 mesothelioma-bearing mice. Feasibility, safety, and effectiveness of virotherapy were assessed by evaluating the peritoneal cancer index (PCI), virus detection in tumor tissues and ascites, virus growth curves, and comparison of overall survival. After i.p. injection of GLV-0b347, virus was detected in both tumor cells and ascites. In comparison to mock-treated mice, overall survival was significantly prolonged, ascites was less frequent and PCI values declined. However, effective treatment was only observed in animals with limited tumor burden at the time point of virus application. Nonetheless, intraperitoneal virotherapy with GLV-0b347 might constitute a novel therapeutic option for the treatment of peritoneal mesothelioma. Additional treatment modifications and combinational regimes will be investigated to further enhance treatment efficacy.

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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.

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2022-04-01 | Intrapleural interleukin-2–expressing oncolytic virotherapy enhances acute antitumor effects and T-cell receptor diversity in malignant pleural disease

ObjectiveThe mainstay of treatment for patients with malignant pleural disease is fluid drainage and systemic therapy. A tumor-specific oncolytic virus or T-cell–activating interleukin-2 immunotherapy may provide an opportunity for local control. We previously developed a vaccinia virus–expressing interleukin-2, an oncolytic virus that mediated tumor regression in preclinical peritoneal tumor models with expansion of tumor-infiltrating lymphocytes. We evaluated the antitumor efficacy and immune modulatory effects of vaccinia virus–expressing interleukin-2 in malignant pleural disease.MethodsA murine model of malignant pleural disease was established with percutaneous intrapleural deposition of the Lewis lung carcinoma cell line and monitored with bioluminescent imaging. After intrapleural or systemic administration of vaccinia viruses (vaccinia virus yellow fluorescent protein control, vaccinia virus–expressing interleukin-2), systemic anti–programmed cell death-1 antibody, or combination therapy (vaccinia virus–expressing interleukin-2 and anti–programmed cell death-1), tumor mass, immune cell infiltration, T-cell receptor diversity, and survival were assessed.ResultsIntrapleural vaccinia virus resulted in significant tumor regression compared with phosphate-buffered saline control (P < .05). Inclusion of the interleukin-2 transgene further increased intratumoral CD8+ T cells (P < .01) and programmed cell death-1 expression on CD8+ tumor-infiltrating lymphocytes (P < .001). Intrapleural vaccinia virus–expressing interleukin-2 was superior to systemic vaccinia virus–expressing interleukin-2, with reduced tumor burden (P < .0001) and improved survival (P < .05). Intrapleural vaccinia virus–expressing interleukin-2 alone or combined treatment with systemic anti–programmed cell death-1 reduced tumor burden (P < .01), improved survival (P < .01), and increased intratumoral αβ T-cell receptor diversity (P < .05) compared with systemic anti–programmed cell death-1 monotherapy.ConclusionsIntrapleural vaccinia virus–expressing interleukin-2 reduced tumor burden and enhanced survival in a murine malignant pleural disease model. Increased CD8+ tumor-infiltrating lymphocytes and αβ T-cell receptor diversity are associated with enhanced response. Clinical trials will enable assessment of intrapleural vaccinia virus–expressing interleukin-2 therapy in patients with malignant pleural disease.

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2021-03-02 | Oncolytic adenovirus: A tool for reversing the tumor microenvironment and promoting cancer treatment (Review)

Immunogene therapy can enhance the antitumor immune effect by introducing genes encoding co‑stimulation molecules, cytokines, chemokines and tumor‑associated antigens into treatment cells or human cells through genetic engineering techniques. Oncolytic viruses can specifically target tumor cells and replicate indefinitely until they kill tumor cells. If combined with immunogene therapy, oncolytic viruses can play a more powerful antitumor role. The high pressure, hypoxia and acidity in the tumor microenvironment (TME) provide suitable conditions for tumor cells to survive. To maximize the potency of oncolytic viruses, various methods are being developed to promote the reversal of the TME, thereby maximizing transmission of replication and immunogenicity. The aim of the present review was to discuss the basic mechanisms underlying the effects of oncolytic adenoviruses on the TME, and suggest how to combine the modification of the adenovirus with the TME to further combat malignant tumors.

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2021-02-18 | In Vivo Priming of Peritoneal Tumor-Reactive Lymphocytes With a Potent Oncolytic Virus for Adoptive Cell Therapy

Adoptive cell therapy (ACT) using autologous tumor infiltrating lymphocytes (TIL) achieves durable clinical benefit for patients from whom these cells can be derived in advanced metastatic melanoma but is limited in most solid tumors as a result of immune escape and exclusion. A tumor microenvironment (TME) priming strategy to improve the quantity and quality of TIL represents an important tactic to explore. Oncolytic viruses expressing immune stimulatory cytokines induce a potent inflammatory response that may enhance infiltration and activation of T cells. In this study, we examined the ability of an attenuated oncolytic vaccinia virus expressing IL15/IL15Rα (vvDD-IL15/Rα) to enhance recovery of lavage T cells in peritoneal carcinomatosis (PC). We found that intraperitoneal (IP) vvDD-IL15/Rα treatment of animals bearing PC resulted in a significant increase in cytotoxic function and memory formation in CD8+ T cells in peritoneal fluid. Using tetramers for vaccinia virus B8R antigen and tumor rejection antigen p15E, we found that the expanded population of peritoneal CD8+ T cells are specific for vaccinia or tumor with increased tumor-specificity over time, reinforced with viral clearance. Application of these vvDD-IL15/Rα induced CD8+ T cells in ACT of a lethal model of PC significantly increased survival. In addition, we found in patients with peritoneal metastases from various primary solid tumors that peritoneal T cells could be recovered but were exhausted with infrequent tumor-reactivity. If clinically translatable, vvDD-IL15/Rα in vivo priming would greatly expand the number of patients with advanced metastatic cancers responsive to T cell therapy.

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2025-11-22 | A novel malignant mesothelioma organoids-T cell co-culture platform for personalized immunochemotherapy testing.

Malignant mesothelioma (MM) is a rare, aggressive cancer with poor outcomes due to its heterogeneity and therapy resistance. Patient-derived organoids (PDOs) have emerged as a promising tool for precision medicine, as they faithfully recapitulate key tumor characteristics. This study aimed to establish MM PDOs and develop a PDO-T cell co-culture system to evaluate their utility in guiding personalized MM treatment. MM PDOs were generated from malignant ascites, pleural effusions, fine-needle biopsies, and surgical tissues. Organoids were characterized using H&E staining, immunohistochemistry (IHC), and next-generation sequencing (NGS). PBMC-derived T cells were co-cultured with PDOs to assess immunotherapy and chemotherapy responses. Drug sensitivity testing was performed to evaluate treatment efficacy. 11 MM PDOs were successfully established, which recapitulated the histological features and genomic profiles of their parental tumors. Drug sensitivity testing revealed heterogeneous responses of PDOs, with sensitivity to anlotinib but resistance to cisplatin plus pemetrexed plus bevacizumab. Notably, PDOs established from the same patient at different time points displayed dynamic changes in genetic profiles and drug sensitivities, mirroring in vivo tumor progression. In the PDO-T cell co-culture system, anti-PD-1 immunotherapy, especially combined with chemotherapy, significantly reduced organoids viability of patient PM002. MM PDOs and the PDO-T cell co-culture system constitute robust models for investigating tumor progression, drug responses, and immunotherapy efficacy. These tools highlight their potential in advancing personalized medicine for MM.

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2025-11-04 | Dynamic evolution of NK cells and immune remodeling mediated by CRS + HIPEC: prognostic mechanisms and therapeutic implications for malignant peritoneal mesothelioma.

Malignant peritoneal mesothelioma (MPM) is a highly aggressive peritoneal malignancy with a significant recurrence rate following cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC). There is an urgent need to investigate novel therapeutic strategies for MPM. Natural killer (NK) cells exhibit rapid responsiveness in anti-tumor immunity; however, NK cells' dynamic evolution and clinical significance in MPM remain unclear. This study retrospectively enrolled 80 newly diagnosed MPM patients (preoperative group) and 64 patients who underwent CRS + HIPEC (postoperative group). The level of NK cells (CD3-CD56dimCD16+) in peripheral blood was quantified using flow cytometry. Univariate and multivariate regression analyses were performed to evaluate the association between NK cell counts and clinicopathological characteristics, intraoperative events, and prognosis. A multivariate prediction model for NK cell recovery was established. 41 patients (51.3%) exhibited decreased NK cell levels preoperatively, which were significantly associated with an increased risk of thrombosis (P = 0.023), intraoperative plasma transfusion (P = 0.004), and prolonged hospitalization duration (P = 0.023). Postoperative dynamic changes in NK cell levels were found to correlate with Karnofsky performance scale (KPS) scores (P = 0.048) and elevated levels of IL-4, IL-5, IL-6, and IL-8 (P < 0.05). Multivariate analysis revealed that the volume of intraoperative plasma transfusion was an independent correlated factor for preoperative NK cell reduction (P = 0.013), while a low KPS score was an independent predictor of postoperative NK cell decline (P = 0.048). Survival analysis indicated that a high perioperative stress score (PSS) (P = 0.015), lymph node metastasis (P = 0.015), significant intraoperative blood loss (P = 0.013), low preoperative CD8⁺ T cell levels (P = 0.001), and reduced postoperative IL-17 expression (P = 0.013) were independent adverse prognostic factors for overall survival (OS). Furthermore, the dynamic NK cell recovery model demonstrated that baseline NK cell levels, peritoneal cancer index (PCI), CD8⁺ T cell status, and postoperative recovery time all significantly influenced the immune remodeling process (all P < 0.001). Preoperative NK depletion correlated with thrombosis and surgical risks, while postoperative NK recovery was influenced by KPS, specific cytokines (IL-4/5/6/8), and was significantly enhanced after CRS + HIPEC.

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2025-09-22 | Elevated Proportion of Tumor-Infiltrating Natural Killer Cells Predicts Improved Survival in Peritoneal Mesothelioma: A Single-Center Study of 109 Cases.

Peritoneal mesothelioma (PeM) is an aggressive malignancy with a dismal prognosis and limited therapeutic options. Tumor-infiltrating natural killer (NK) cells play a pivotal role in anti-tumor immunity, yet their clinical significance in PeM remains unclear. This study aimed to investigate the correlation between NK cell infiltration levels and the main clinicopathologic characteristics and prognosis in PeM. The study collected 109 postoperative specimens from PeM patients after cytoreductive surgery. Immunohistochemical staining was performed, and NK cell infiltration was quantified using QuPath-0.3.2 software. Uni- and multivariate analyses were performed to assess correlations between NK infiltration levels and clinicopathologic parameters. The 109 PeM patients in the study included 52 males (47.7%) and 57 females (52.3%) with a median age of 54 years (range, 25-72 years). Levels of NK infiltration were found to be low in 54 (49.5%) cases and high in 55 (50.5%) cases. Univariate analysis showed that a high NK infiltration level was negatively associated with the following five clinicopathologic factors: preoperative carbohydrate antigen (CA) 125 level, completeness of cytoreduction (CC), bleeding, red blood cell (RBC) transfusion, and ascites (all P < 0.05). Additionally. survival analysis demonstrated that a high NK infiltration level was associated with a better prognosis. Tumor-infiltrating NK cells may serve as prognostic biomarkers and guide personalized treatment strategies for PeM patients.

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2025-05-15 | Clinical Significance of Tumor-Infiltrating Lymphocytes in Malignant Peritoneal Mesothelioma: A Single-Center Study of 143 Cases.

Malignant peritoneal mesothelioma (MPM) is a rare malignant tumor with high mortality rate and extremely poor prognosis. The tumor immune microenvironment, particularly tumor-infiltrating lymphocytes (TILs), plays a critical role in disease progression and treatment response. This study aimed to analyze the correlation between the level of TILs and the main clinicopathological characteristics and prognosis of MPM. A total of 143 postoperative specimens from patients with MPM following cytoreductive surgery were collected. Postoperative specimens were stained with hematoxylin and eosin (H&E). The level of TILs was quantitatively analyzed by QuPath 0.3.2 software. Univariate and multivariate analyses were conducted to investigate the correlation between TILs level and other conventional clinicopathological characteristics. Among the 143 patients with MPM, 73 were male (51.0%) and 70 were female (49.0%), with a median age of 55 (range 24-73) years. There were 72 (50.3%) cases with low TILs, and 71 (49.7%) cases with high TILs. Univariate analysis showed that TIL level (low versus high) was negatively correlated with the following seven clinicopathological factors: surgery history, Ki-67 index, preoperative CA125 level, peritoneal cancer index (PCI) index, bleeding volume, red blood cell (RBC) transfusion volume, and ascites volume (all P < 0.05). Multivariate analysis indicated that TIL level was independently negatively correlated with preoperative carbohydrate antigen (CA)125 level (odds ratio 0.394, 95% CI 0.179-0.866, P = 0.020). Cox regression analysis suggested that high TILs was independently associated with better prognosis of MPM. Moreover, a cohort of patients who received preoperative chemotherapy combined with targeted therapy were evaluated for response. Kaplan-Meier curve showed that high infiltration of TILs predicted better overall survival in patients undergoing treatment. TILs could be a useful indicator for predicting prognosis and guiding personalized treatment strategies in patients with MPM.

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2024-11-01 | Potential treatment approaches for malignant peritoneal mesothelioma: in vivo and in vitro experimental study of natural killer cell immunotherapy.

Malignant peritoneal mesothelioma (MPM) is a rare primary malignant tumor with an extremely poor prognosis that currently lacks effective treatment options. This study investigated the in vitro and in vivo efficacy of natural killer (NK) cells for treatment of MPM. An in vitro study was conducted to assess the cytotoxicity of NK cells from umbilical cord blood to MPM cells with the use of a high-content imaging analysis system, the Cell Counting Kit-8 assay, and Wright-Giemsa staining. The level of NK cell effector molecule expression was detected by flow cytometry and enzyme-linked immunosorbent assays. The ability of NK cells to kill MPM cells was determined based on live cell imaging, transmission electron microscopy, and scanning electron microscopy. An in vivo study was conducted to assess the efficacy and safety of NK cell therapy based on the experimental peritoneal cancer index, small animal magnetic resonance imaging, and conventional histopathologic, cytologic, and hematologic studies. NK cells effectively killed MPM cells through the release of effector molecules (granzyme B, perforin, interferon-γ, and tumor necrosis factor-α) in a dose- and density-dependent manner. The NK cell killing process potentially involved four dynamic steps: chemotaxis; hitting; adhesion; and penetration. NK cells significantly reduced the tumor burden, diminished ascites production, and extended survival with no significant hematologic toxicity or organ damage in NOG mice. NK cell immunotherapy inhibited proliferation of MPM cells in vitro and in vivo with a good safety profile.

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