Oncolytic adenovirus in treating malignant ascites: A phase II trial and longitudinal single-cell study.

Malignant ascites is a common complication resulting from the peritoneal spread of malignancies, and currently lacks effective treatments. We conducted a phase II trial (NCT04771676) to investigate the efficacy and safety of oncolytic adenovirus H101 and virotherapy-induced immune response in 25 patients with malignant ascites. Oncolytic virotherapy achieved an increased median time to repeat paracentesis of 45 days (95% confidence interval 16.5-73.5 days), compared with the preset control value of 13 days. Therapy was well-tolerated, with pyrexia, fatigue, nausea, and abdominal pain as the most common toxicities. Longitudinal single-cell profiling identified marked oncolysis, early virus replication, and enhanced CD8+ T cells-macrophages immune checkpoint crosstalk, especially in responsive patients. H101 also triggered a proliferative burst of CXCR6+ and GZMK+CD8+ T cells with promoted tumor-specific cytotoxicity. Further establishment of oncolytic virus-induced T cell expansion signature (OiTE) implicated the potential benefits for H101-responsive patients from subsequent anti-PD(L)1 therapy. Patients with upregulated immune-signaling pathways in tumor cells and a higher proportion of CLEC10A+ dendritic cells and GZMK+CD8+ T cells at baseline showed a superior response to H101 treatment. Our study demonstrates promising clinical responses and tolerability of oncolytic adenovirus in treating malignant ascites and provides insights into the relevant cellular processes following oncolytic virotherapy.

The complex role of IL-10 in malignant ascites: a review.

The emergence of malignant ascites (MA) indicates poor prognoses in patients with ovarian, gastrointestinal, breast, and pancreatic cancer. Interleukin-10 (IL-10) is a pleiotropic cytokine with immunoregulatory effects in tumor microenvironment. The level of IL-10 in MA varied across cancer types and patients, influencing cancer progression and outcomes. Originating from various immune and cancer cells, IL-10 contributes to complex signaling pathways in MA. Systemic IL-10 administration, although the evidence of its efficacy on MA is limited, still emerges as a promising therapeutic strategy because it can increase CD8+ T cells cytotoxicity and invigorate exhausted CD8+ tumor infiltration lymphocytes (TILs) directly. IL-10 signaling blockade also demonstrates great potential when combined with other immunotherapies in MA treatment. We reviewed the levels, origins, and functions of IL-10 in malignant ascites and overviewed the current IL-10 signaling targeting therapies, aiming to provide insights for MA treatment.

PD-L1+ neutrophils induced NETs in malignant ascites is a potential biomarker in HCC.

BACKGROUND: Since differentiating malignant ascites from benign ascites has always been a clinical difficult, recognition of novel biomarkers in malignant ascites of hepatocellular carcinoma (HCC) patients could be helpful for establishing a diagnosis for HCC patients with ascitic fluids. METHODS: Thirty-five HCC patients with malignant ascites and chronic liver diseases patients with benign ascites were enrolled. Serum and ascites specimens were collected to determine TAN subpopulations and NETs concentration. Then, the correlation between ascitic NETs levels and clinical features were analyzed, and ROC curves were generated to evaluate the diagnostic value of NETs. For in vitro study, fresh neutrophils were employed to explore the underlying mechanism of TAN polarization and NETs formation using RNAseq analysis. RESULTS: Significantly increased pro-tumor PD-L1+ TANs and higher lactate levels were measured in HCC ascites. RNAseq data showed that lactate regulated genes expression involving PD-L1 expression and NETs formation, suggesting that ascitic lactate might be responsible for tumor progression in TME. Then, NETs-related markers including calprotectin, dsDNA, CitH3, MPO and MPO-DNA were found dramatically elevated in malignant ascites. Next, correlation analysis revealed that ascitic NETs levels positively correlated with LDH, a classic ascitic biochemical indicator. Furthermore, we identified the diagnostic values of NETs in discriminating malignant ascites from benign ascites. CONCLUSIONS: Our findings highlighted that elevated ascitic NETs served as a biomarker in HCC patients with malignant ascites, which provided useful insights for both clinical and basic research for malignant ascites diagnosis and management.

Treatment outcomes of gemcitabine plus nab-paclitaxel in pancreatic cancer patients with malignant ascites.

BACKGROUND: Gemcitabine plus nab-paclitaxel (GnP) therapy has been shown to improve the prognosis in patients with metastatic pancreatic cancer (PC); however, the efficacy and safety of GnP in PC patients with malignant ascites (MA) remains unknown. METHODS: We retrospectively investigated PC patients with peritoneal dissemination who had received GnP as first-line chemotherapy at our institution between March 2015 and August 2021. The following patient data were reviewed: patient characteristics, overall survival (OS), progression-free survival (PFS), objective response rate (ORR), adverse events (AEs), and relative dose intensity (RDI). The severity of MA was categorized based on the CT findings as grade 1 (small), grade 2 (moderate), or grade 3 (massive). RESULTS: A total of 189 patients were included; the study endpoints were compared between patients with each ascites grade and 41 patients without MA. The MA was classified as grade 1 in 85 patients, grade 2 in 41 patients, and grade 3 in 22 patients. In the patients with MA, the median OS, PFS and ORR were 11.2 months, 5.7 months and 24.3%, respectively. The OS and PFS decreased with increasing the severity of MA; in particular, patients with grade 2 and 3 showed a poorer prognosis. There were no differences in AEs, except for anorexia, or the RDI according to the severity of MA. CONCLUSION: GnP showed moderate efficacy with manageable safety profile in PC patients with MA. However, PC patients with moderate to massive ascites still have a dismal prognosis, and further development of effective treatments is needed.

Intensifying supportive care is associated with improved survival in gastric cancer patients with malignant ascites.

BACKGROUND: Gastric cancer patients with malignant ascites often have poor functional status and malnutrition that preclude receipt of systemic therapies. Thus, these patients have a very poor prognosis. Beginning in 2019, our multidisciplinary gastric cancer disease-oriented team implemented a more aggressive supportive care plan for gastric cancer patients with malignant ascites. The initiative included measures such as supplemental enteral nutrition, ascites drainage, and initiation of chemotherapy on an inpatient basis. We compared outcomes for gastric cancer patients who presented with synchronous malignant ascites treated before and after the implementation of the care plan. METHODS: We performed a retrospective review of our institutional database to identify patients diagnosed with gastric adenocarcinoma and synchronous malignant ascites between 2010 and 2022. We compared overall survival (OS) between patients diagnosed from 2010 to 2018, which will be referred to as the historical control era and patients diagnosed from 2019 to 2022, which will be called the aggressive supportive care era. RESULTS: Fifty-four patients were included in our analysis; 31 patients were treated in the historical control time frame, and 23 patients were treated during the aggressive supportive care era. Demographic, clinical, and pathologic characteristics were similar between groups. 3% of historical controls received supplemental tube feeds at diagnosis as compared to 30% of the aggressive supportive care cohort (p < 0.01). 3% of historical controls received their first cycle of chemotherapy in the inpatient setting versus 39% of patients treated during the aggressive supportive care era (p < 0.01). The median number of chemotherapy cycles received was 5 among historical controls and 9.5 among aggressive supportive care era patients (p = 0.02). There was no difference in the number of days spent as an inpatient between the two groups. The median OS for historical control patients was 5.4 months as compared with 10.4 months for patients treated during aggressive supportive care era (p = 0.04). CONCLUSIONS: Gastric cancer patients with synchronous malignant ascites treated during a timeframe when our multidisciplinary team implemented more aggressive supportive care measures had improved OS as compared with historic controls. Our results suggest that aggressive supportive measures for these patients with highly challenging clinical issues and poor prognosis can prolong survival. Specifically, initiation of chemotherapy in the inpatient setting and supplemental nutrition should be considered for patients at high risk for treatment intolerance.

Advances in the treatment of malignant ascites in China.

PURPOSE: Malignant ascites (MA) often occurs in recurrent abdominal malignant tumors, and the large amount of ascites associated with cancerous peritonitis not only leads to severe abdominal distension and breathing difficulties, but also reduces the patient's quality of life and ability to resist diseases, which usually makes it difficult to carry out anti-cancer treatment. The exploration of MA treatment methods is also a key link in MA treatment. This article is going to review the treatment of MA, to provide details for further research on the treatment of MA, and to provide some guidance for the clinical treatment of MA. METHOD: This review analyzes various expert papers and summarizes them to obtain the paper. RESULT: There are various treatment methods for MA, including systemic therapy and local therapy. Among them, systemic therapy includes diuretic therapy, chemotherapy, immunotherapy, targeted therapy, anti angiogenic therapy, CAR-T, and vaccine. Local therapy includes puncture surgery, peritoneal vein shunt surgery, acellular ascites infusion therapy, radioactive nuclide intraperitoneal injection therapy, tunnel catheter, and intraperitoneal hyperthermia chemotherapy. And traditional Chinese medicine treatment has also played a role in enhancing efficacy and reducing toxicity to a certain extent. CONCLUSION: Although there has been significant progress in the treatment of MA, it is still one of the clinical difficulties. Exploring the combination or method of drugs with the best therapeutic effect and the least adverse reactions to control MA is still an urgent problem to be solved.

Soluble factors in malignant ascites promote the metastatic adhesion of gastric adenocarcinoma cells.

BACKGROUND: Adenocarcinoma of the proximal stomach is the fastest rising malignancy in North America. It is commonly associated with peritoneal accumulation of malignant ascites (MA), a fluid containing cancer and inflammatory cells and soluble proteins. Peritoneal metastasis (PM) is the most common site of gastric cancer (GC) progression after curative-intent surgery and is the leading cause of death among GC patients. METHODS/RESULTS: Using a panel of gastric adenocarcinoma cell lines (human: MKN 45, SNU-5; murine: NCC-S1M), we demonstrate that prior incubation of GC cells with MA results in a significant (> 1.7-fold) increase in the number of cells capable of adhering to human peritoneal mesothelial cells (HPMC) (p < 0.05). We then corroborate these findings using an ex vivo PM model and show that MA also significantly enhances the ability of GC cells to adhere to strips of human peritoneum (p < 0.05). Using a multiplex ELISA, we identify MIF and VEGF as consistently elevated across MA samples from GC patients (p < 0.05). We demonstrate that agents that block the effects of MIF or VEGF abrogate the ability of MA to stimulate the adhesion of GC cells to adhere to human peritoneum and promote both ex vivo and in vivo metastases. CONCLUSION: Agents targeting MIF or VEGF may be relevant to the treatment or prevention of PM in GC patients.

Hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy for the malignant effusion: a multi-center randomized clinical trial.

OBJECTIVE: To compare the efficacy and safety of hyperthermic intrathoracic/intraperitoneal chemotherapy versus conventional intrapleural/intraperitoneal chemotherapy in the treatment of malignant pleural or peritoneal effusion. METHODS: A randomized clinical trial was carried out in 8 cancer centers across China. Patients with malignant pleural or peritoneal effusion were randomly assigned to the study group or control group. Patients in the study group were treated with cisplatin-based hyperthermic intrathoracic chemotherapy (HITHOC) or hyperthermic intraperitoneal chemotherapy (HIPEC), while the control group was treated with conventional intrapleural or intraperitoneal chemotherapy using same chemotherapeutic regime as the study group. The objective response rate (ORR) was analyzed as primary outcome. Quality-of-life (QOL) score was recorded as secondary outcome using the questionnaire 30 (QLQ-C30) of the European Organization for Research and Treatment of Cancer (EORTC). The efficacy and safety of the two treatments were compared. RESULTS: Total 135 patients were recruited and randomized in this study, with 67 patients in the study group and 68 patients in the control group. The ORR in the study group (80.70%) was significantly higher than that in the control group (31.03%, p < 0.001). However, neither changes of QOL scores, nor incidence rates of adverse events were significantly different between the two groups (p = 0.076 and 0.197, respectively). CONCLUSION: Efficacy of HITHOC or HIPEC is superior to that of conventional modality for the treatment of malignant effusion with comparable side effects.

Anti-Tumor Immunogenicity of the Oncolytic Virus CF33-hNIS-antiPDL1 against Ex Vivo Peritoneal Cells from Gastric Cancer Patients.

We studied the immunotherapeutic potential of CF33-hNIS-antiPDL1 oncolytic virus (OV) against gastric cancer with peritoneal metastasis (GCPM). We collected fresh malignant ascites (MA) or peritoneal washings (PW) during routine paracenteses and diagnostic laparoscopies from GC patients (n = 27). Cells were analyzed for cancer cell markers and T cells, or treated with PBS, CF33-GFP, or CF33-hNIS-antiPDL1 (MOI = 3). We analyzed infectivity, replication, cytotoxicity, CD107α upregulation of CD8+ and CD4+ T cells, CD274 (PD-L1) blockade of cancer cells by virus-encoded anti-PD-L1 scFv, and the release of growth factors and cytokines. We observed higher CD45-/large-size cells and lower CD8+ T cell percentages in MA than PW. CD45-/large-size cells were morphologically malignant and expressed CD274 (PD-L1), CD252 (OX40L), and EGFR. CD4+ and CD8+ T cells did not express cell surface exhaustion markers. Virus infection and replication increased cancer cell death at 15 h and 48 h. CF33-hNIS-antiPDL1 treatment produced functional anti-PD-L1 scFv, which blocked surface PD-L1 binding of live cancer cells and increased CD8+CD107α+ and CD4+CD107α+ T cell percentages while decreasing EGF, PDGF, soluble anti-PD-L1, and IL-10. CF33-OVs infect, replicate in, express functional proteins, and kill ex vivo GCPM cells with immune-activating effects. CF33-hNIS-antiPDL1 displays real potential for intraperitoneal GCPM therapy.

Feasibility of a fast-track randomized controlled trial of cell-free and concentrated ascites reinfusion therapy for patients with refractory malignant ascites.

BACKGROUND: Malignant ascites often causes discomfort in advanced cancer patients. Paracentesis is the most common treatment modality, but it requires frequently repeated treatment. Cell-free and concentrated ascites reinfusion therapy (CART) may prolong the paracentesis interval, but controlled trials are lacking. We assessed the feasibility of a randomized controlled trial of CART vs. paracentesis alone for patients with refractory malignant ascites. METHODS: This study was an open-label, fast-track, randomized controlled, feasibility trial. Patients admitted to four designated cancer hospitals who received no further anticancer treatments were eligible. Patients were randomly assigned 1:1 to a CART arm or control (simple paracentesis) arm. The feasibility endpoint was the percentage of patients who completed the study intervention. Secondary endpoints included paracentesis-free survival, patient's request on the questionnaire for paracentesis (PRO-paracentesis)-free survival (the period until the patients first reported that they would want paracentesis if indicated), and adverse events. RESULTS: We screened 953 patients for eligibility. Of 61 patients with refractory malignant ascites, 21 patients were determined as eligible. Finally, 20 patients consented and were allocated; 18 patients (90%, 95% CI: 68.3-98.8) completed the study intervention. All patients had an ECOG performance status of 3 or 4. The median drained ascites volume was 3,200 mL in the CART arm and 2,500 mL in the control arm. In the CART arm, the median reinfused albumin volume was 12.6 g. Median paracentesis-free survivals were 5 days (95% CI: 2-6) in the CART arm, and 6 days (3-9) in the control arm. Median PRO-paracentesis-free survivals were 4 days (2-5) and 5 days (1-9), respectively. A total of 73% of patients received paracentesis within 2 days from their first request for the next paracentesis. One patient in the CART arm developed Grade 1 fever. CONCLUSIONS: A fast-track randomized controlled trial of CART for patients with malignant ascites is feasible. The efficacy and safety of CART should be assessed in future trials. PRO-paracentesis-free survival may be a complementary outcome measure with paracentesis-free survival in future trials. TRIAL REGISTRATION: Registered at University Hospital Medical Information Network Clinical Trial Registry as UMIN000031029 . Registered on 28/01/2018.