361 A randomised open-label phase I/II study adding ONCOS-102 to pemetrexed/cisplatin in patients with unresectable malignant pleural mesothelioma – 12 month analysis of biomarkers and clinical outcomes

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A386-A386
Author(s):  
Magnus Jaderberg ◽  
Susana Cedres ◽  
Luis Paz-Ares ◽  
Xavier Serres ◽  
Charles Ricordel ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Malignant Pleural Mesothelioma ◽  
Immune Activation ◽  
Checkpoint Inhibitors ◽  
Macrophage Polarization ◽  
Control Group ◽  
Pleural Mesothelioma ◽  
Immunological Activation ◽  
M1 Macrophage ◽  
Experimental Group

BackgroundMalignant pleural mesothelioma (MPM) is a rare, aggressive malignancy without curative treatment. Majority of patients receive pemetrexed/cisplatin as standard of care (SoC). Median overall survival in unresectable disease is 12 months. ONCOS-102 is a granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic adenovirus (Ad5/3-D24-GMCSF) with a unique ability to both prime and boost immune responses. The aim of the study was to assess immune and clinical responses as well as safety in patients with 1st and 2nd line unresectable MPM.MethodsEligible patients (experimental arm, n=20) received ONCOS-102 given intratumorally under CT or US guidance at a dose of 3 × 10 × 11 on Day 1, 4, 8, 36, 78 and 120 plus six cycles of SoC starting on Day 22. The control group (n=11) received only SoC. Imaging was done at baseline, Day 43–64 and 127–148. Patients were monitored regularly for immunological assessment including lesional biopsies (baseline and Day 36). Primary objective was safety and tolerability. Secondary objectives were immunological activation, ORR, PFS and OS as well as correlation between immunological activation and clinical outcome.ResultsThere were no safety concerns nor DLTs. In 1st line patients ORR/DCR was 30%/90% in the experimental group and 33%/83% in the control group. 2nd line patients had ORR/DCR of 11%/67% in the experimental group and 60%/80% in the control group. 12-month survival rate for the 1st line pts was 64% in the experimental group and 50% in the control group. PFS and OS are still to be reported. The treatment with ONCOS-102 induced strong upregulation of multiple genes associated with immune activation in tumor lesions. Profound innate and adaptive immune activation was observed in the experimental vs control group that was associated with better clinical outcome. In addition to an increase in intra-tumoral cytotoxic T-cells (10/15 pts), the treatment with ONCOS-102 resulted in polarization from M2 to M1 macrophages. An upregulation of PD-L1 was reported in 9/15 pts in the experimental group vs 2/5 pts in the control arm, highlighting the potential of ONCOS-102 as an immunosensitizing agent for combinatory therapies with checkpoint inhibitors.ConclusionsONCOS-102 treated patients benefited from superior immune activation compared to patients receiving SoC with preliminary signals of clinical efficacy. Upregulation of adaptive immunity and cytotoxicity related gene expression, PD-L1 level and M2 to M1 macrophage polarization indicate that ONCOS-102 can induce a favourable TME modulation thus providing a scientific rationale for combination with check point inhibition.Trial RegistrationClinicalTrials. gov NCT02879669Ethics ApprovalThis study was approved by the IRBs of all the sites in Madrid, Barcelona, Rennes and Poitiers.

scholarly journals 462 A randomised open-label phase I/II study adding ONCOS-102 to pemetrexed/cisplatin in patients with unresectable malignant pleural mesothelioma – 24 month survival data

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A491-A491
Author(s):  
Magnus Jaderberg ◽  
Luis Paz-Ares ◽  
Susana Cedres ◽  
Charles Ricordel ◽  
Nicolas Isambert ◽  
...  
Keyword(s):  
Survival Rate ◽  
Malignant Pleural Mesothelioma ◽  
Survival Data ◽  
Phase Iii ◽  
Control Group ◽  
Pleural Mesothelioma ◽  
List Type ◽  
Open Label ◽  
Open Label Phase ◽  
Experimental Group

BackgroundMalignant pleural mesothelioma (MPM) is an aggressive malignancy without curative treatment. Standard of care (SOC) include pemetrexed/cisplatin and nivolumab/ipilimumab with median overall survival in unresectable disease of 12.1 months and 18.1 months respectively.1 2 ONCOS-102 is a granulocyte-macrophage colony stimulating factor (GM-CSF) expressing oncolytic adenovirus (Ad5/3-D24-GMCSF) with a unique ability to both prime and boost immune responses. The aim of the study was to assess efficacy and safety of ONCOS-102 in combination with SOC chemotherapy in 1st and 2nd line unresectable MPM.MethodsTwenty patients (experimental arm) were allocated to receive ONCOS-102 given intratumorally under CT or US guidance at a dose of 3 x 1011 VP on Day 1, 4, 8, 36, 78 and 120 plus six cycles of SOC starting on Day 22. Eleven patients (control group) received SOC. Imaging was done at baseline, Day 43–64 and 127–148 with regular monitoring of blood and biopsy based immune markers. Primary objective was safety and tolerability. Secondary objectives were ORR, PFS and OS as well as immunological activation. An analysis of 24 month survival data compared randomised only patients excluding six patients in the single-arm safety lead-in.Results24-month survival rate for 1st line pts was 50% in the experimental group and 0% in the control group with mOS of 25.0 months and 13.5 months respectively (N.S). Based on censoring, mOS in the experimental group will be within 21.9 – 25.0 months range. mOS across both 1st and 2nd line was 19.3 and 18.3 months for experimental and control patients (N.S). mPFS was 9.8 months in the experimental group and 7.6 in the control group (N.S.).ConclusionsThe survival rate of patients receiving ONCOS-102 in combination with SOC was seen to be numerically higher than previously reported for SOC or nivolumab/ipilimumab. Improved survival was associated with ONCOS-102 induced immune activation with a favourable TME modulation providing scientific rationale for combination with check point inhibition.Trial RegistrationClinicalTrials.gov NCT02879669ReferencesVogelzang, et al, Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol 2003;21: 2636–44.Baas P, et al, First-line nivolumab plus ipilimumab in unresectable pleural mesothelioma (CheckMate 743): a multicentre, randomised, open-label, phase 3 trial. The Lancet 2021; 397: 375–386.Ethics ApprovalThis study was approved by the IRBs of all the participating sites in Madrid, Barcelona, Rennes and Poitiers.

scholarly journals Radical Hemithoracic Radiotherapy Induces Systemic Metabolomics Changes That Are Associated with the Clinical Outcome of Malignant Pleural Mesothelioma Patients

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 508
Author(s):  
Emanuela Di Gregorio ◽  
Gianmaria Miolo ◽  
Asia Saorin ◽  
Elena Muraro ◽  
Michela Cangemi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Overall Survival ◽  
Clinical Outcome ◽  
Malignant Pleural Mesothelioma ◽  
Therapeutic Option ◽  
Enrichment Analysis ◽  
Metabolic Effects ◽  
Pleural Mesothelioma ◽  
Polyamine Biosynthesis ◽  
The Individual

Radical hemithoracic radiotherapy (RHRT) represents an advanced therapeutic option able to improve overall survival of malignant pleural mesothelioma patients. This study aims to investigate the systemic effects of this radiotherapy modality on the serum metabolome and their potential implications in determining the individual clinical outcome. Nineteen patients undergoing RHRT at the dose of 50 Gy in 25 fractions were enrolled. Serum targeted metabolomics profiles were investigated at baseline and the end of radiotherapy by liquid chromatography and tandem mass spectrometry. Univariate and multivariate OPLS-DA analyses were applied to study the serum metabolomics changes induced by RHRT while PLS regression analysis to evaluate the association between such changes and overall survival. RHRT was found to affect almost all investigated metabolites classes, in particular, the amino acids citrulline and taurine, the C14, C18:1 and C18:2 acyl-carnitines as well as the unsaturated long chain phosphatidylcholines PC ae 42:5, PC ae 44:5 and PC ae 44:6 were significantly decreased. The enrichment analysis showed arginine metabolism and the polyamine biosynthesis as the most perturbed pathways. Moreover, specific metabolic changes encompassing the amino acids and acyl-carnitines resulted in association with the clinical outcome accounting for about 60% of the interpatients overall survival variability. This study highlighted that RHRT can induce profound systemic metabolic effects some of which may have a significant prognostic value. The integration of metabolomics in the clinical assessment of the malignant pleural mesothelioma could be useful to better identify the patients who can achieve the best benefit from the RHRT treatment.

Experimental study of the inhibition effect of CXCL12/CXCR4 in malignant pleural mesothelioma

2018 ◽  
Vol 67 (2) ◽  
pp. 338-345 ◽  
Author(s):  
Jianshuang Li ◽  
Tong Li ◽  
Shuo Li ◽  
Lipeng Xie ◽  
Yi-Lin Yang ◽  
...  
Keyword(s):  
Treatment Group ◽  
Malignant Pleural Mesothelioma ◽  
Synergistic Effects ◽  
Control Group ◽  
Pleural Mesothelioma ◽  
Gene Expressions ◽  
Relationship Of ◽  
The Relationship ◽  
Cxcr4 Axis

Previous studies have demonstrated that CXCL12/CXCR4 axis is closely related to tumors such as malignant pleural mesothelioma (MPM). This research was conducted in order to detect whether CXCL12/CXCR4 inhibitors could restrain MPM and have a synergistic effect with chemotherapy, also to investigate the relationship of CXCL12/CXCR4 with other gene expressions in MPM. Forty mice were injected MPM cells and randomly divided into four groups: the PBS (control group), AMD3100 (CXCR4-CXCL12 antagonist), pemetrexed and AMD3100 plus pemetrexed. The mice were treated respectively for duration of 3 weeks. The size, bioluminescence and weight of tumors were measured. The differences between gene expressions in each group were analyzed. The tumor weights of each treatment group were lower than that of the control group (p<0.05). The bioluminescence of the tumor of the AMD3100 treatment group and the AMD3100 plus pemetrexed treatment group were lower than that of the control group (p<0.05), and AMD3100 was shown to have synergistic effects with pemetrexed (p<0.05). Among the 2.5 billion genes, several hundreds of genes expressed differently between groups. Results show that AMD3100 and pemetrexed can inhibit the growth of MPM in vivo, also that there is a better result if both are used together. Our findings suggest that CXCL12/CXCR4 axis affects a certain amount of gene expression in MPM.

Immunotherapy experience in malignant pleural mesothelioma in a single tertiary center.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20565-e20565
Author(s):  
Ervin Saúl Enciso López ◽  
Efrain Isaias Camarin Sanchez ◽  
Daniela Vazquez Juarez ◽  
Alejandro Noguez-Ramos ◽  
Daniela Shveid Gerson ◽  
...  
Keyword(s):  
Malignant Pleural Mesothelioma ◽  
Checkpoint Inhibitors ◽  
Cancer Prognosis ◽  
Clinical Response Rate ◽  
Pleural Mesothelioma ◽  
Heavy Smoking ◽  
Identifiable Risk Factor ◽  
Pathologic Features ◽  
Number Of Patients ◽  
Tertiary Center

e20565 Background: Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer. Prognosis is generally poor, with a median overall survival (mOS) of approximately 12 months. MPM appears to be directly linked to immunosuppressive mechanisms, leading to use of checkpoint inhibitors for patients with this disease. Methods: We performed a retrospective chart review of patients with MPM at our institution between January 2015 to December 2020. All patients were over 18 years at the time of diagnosis of mesothelioma, a total of 8 patients were retrieved from the pathology database of The American British Cowdray Medical Center. The clinical-pathologic features collected were sex, age, performance status, risk factors, pTNM stage (AJCC 8th edition), histology type, sintomatology of onset, metastases sites and treatment. Clinical response rate and other outcomes were assessed. Descriptive statistics were used to describe a patient's demographic and disease characteristics. Results: 8 patients, aged 49 to 71 years (median of 65) at diagnosis of MPM were treated in our center. Both sex presented 4 patients in total. An identifiable risk factor was recorded in 4 patients (2 with asbesto exposure and 2 with heavy smoking). 7 patients (87.5%) had PS 0 or 1, the remaining has PS 2. The clinical stage at diagnosis was unresectable in 7 patients. 3 patients were assessed with PD-L1 expression (SP263 or 22C3), only one with expression of 20%. All patients received at least one scheme of chemotherapy prior to receiving immunotherapy, 25% received bevacizumab/platinum/anti-folate agents. Checkpoint inhibitors were introduced as a second line in 20% and in 80% has a third or more lines. Pembrolizumab was used in 20% and Nivolumab in 80%. The tumor responses with immunotherapy were as follows: partial response 12.5%, stable disease 75% and progressive disease 12.5%. Median progression-free survival of the first line treatment was 18.9 months (4.6-33.6 months), and for the line with checkpoint inhibitors was 11.2 weeks (7-21.2). In the full cohort, mOS was 37.0 months (95% CI:14.5-39.6). According to histology, the mOS for epithelioid-type was 36.6 months and for biphasic-type was 14.6 months (p = 0.42). mOS was 37.0 months for the group with immunotherapy and 15.0 months for those with standard chemotherapy (p = 0.14). The most frequently reported immune mediated adverse events were hypothyroidism and colitis (each one with one patient). Conclusions: In this real-world analysis, mOS was superior to those obtained in the MAPS2 trial (mOS 11.9 months), despite the fact that 80% of the population that received immunotherapy was in third or more lines. Limitations include limited numbers of patients, retrospective review, single institution, and inclusión of many heavily pretreated patients. Also molecular and immunohistochemical results such as PD-L1 status were only available on a limited number of patients.

Phase Ib/II open-label, randomized evaluation of atezolizumab (atezo) + Imprime PGG (Imprime) + bevacizumab (bev) vs regorafenib (rego) in MORPHEUS: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3559-3559
Author(s):  
Marwan Fakih ◽  
James M. Cleary ◽  
Yong Sang Hong ◽  
Tae-You Kim ◽  
Rachael A Safyan ◽  
...  
Keyword(s):  
Stable Disease ◽  
Checkpoint Inhibitors ◽  
Macrophage Polarization ◽  
Objective Response ◽  
Systemic Exposure ◽  
Progression Free Survival ◽  
Open Label ◽  
Multikinase Inhibitor ◽  
Phase Ib ◽  
M1 Macrophage

3559 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to identify early efficacy and safety signals of treatment (tx) combinations across cancers. Here, atezo (anti-PD-L1) was tested with Imprime and bev (anti-VEGF) for MSS mCRC, a poorly immunogenic cancer generally resistant to checkpoint inhibitors. Imprime acts as a pathogen-associated molecular pattern that, when bound to anti-β glucan antibodies (ABA), activates the innate immune system with the potential to 1) promote priming and expansion of tumor-specific T cells, 2) promote M2-M1 macrophage polarization and 3) enhance the immunomodulatory effects of atezo and bev. Therefore, we hypothesized that atezo + Imprime + bev would induce an antitumor response beyond that of rego, a standard-of-care multikinase inhibitor, in patients (pts) with MSS mCRC. Methods: Pts with MSS mCRC unselected for the Imprime-specific biomarker (ABA) and refractory to 1-2 prior lines of standard therapy received atezo (1200 mg IV every 3 weeks [q3w]) + Imprime (4 mg/kg IV on Days 1, 8, 15) + bev (7.5 mg/kg IV q3w) or control tx with rego (160 mg orally days 1-21; dose escalation to 160 mg during Cycle 1 allowed per institutional guidelines). The primary endpoint was objective response rate (ORR; investigator-assessed RECIST 1.1); secondary endpoints included disease control rate (DCR; response or stable disease ≥ 12 weeks), progression-free survival (PFS), overall survival (OS) and safety. Results: Pts were followed-up for ≥18 wk. 15 pts received atezo + Imprime + bev and 13 received rego. Grade (Gr) 3/4 tx-related adverse events (TRAEs) were seen in 13% of atezo + Imprime + bev and 62% of rego pts. No Gr 5 AEs occurred in atezo + Imprime + bev pts and 1 (8%) was reported in a rego pt. One pt in each arm (7% vs 8%, respectively) withdrew from tx due to a TRAE. No radiological responses were seen in either arm. Five pts (33%) receiving atezo + Imprime + bev and 8 (62%) receiving rego had stable disease as best response. DCR was 13% with atezo + Imprime + bev and 23% with rego. Median PFS was 1.5 mo (95% CI: 1.4, 2.8) and 2.8 mo (95% CI: 1.6, 3.1), and median OS was 5.7 mo (95% CI: 4.4, 10.5) and 10.2 mo (95% CI: 4.8, NE) with atezo + Imprime + bev and rego, respectively. There was no apparent correlation between baseline PD-L1 expression or CD8+ lymphocyte tumor infiltration and clinical benefit. Further, the systemic exposure of atezo, Imprime and bev and immunogenicity of atezo and bev are in line with previous clinical experience. Additional biomarker, pharmacokinetics and anti-drug antibody data will be shown. Conclusions: Atezo + Imprime + bev was well tolerated; toxicities were consistent with the safety profiles of the individual agents. No efficacy signal was identified with atezo + Imprime + bev in pts with MSS refractory mCRC. Clinical trial information: NCT03555149.

scholarly journals P3.03-042 Study Comparing Volume and TNM in Predicting Clinical Outcome in Malignant Pleural Mesothelioma

2017 ◽  
Vol 12 (1) ◽  
pp. S1371
Author(s):  
Claudia Proto ◽  
Diego Signorelli ◽  
Sandra Mallone ◽  
Francesca Greco ◽  
Giuseppina Calareso ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Malignant Pleural Mesothelioma ◽  
Pleural Mesothelioma

scholarly journals Matrix metalloproteinases polymorphisms as baseline risk predictors in malignant pleural mesothelioma

2018 ◽  
Vol 0 (0) ◽  
Author(s):  
Danijela Strbac ◽  
Katja Goricar ◽  
Vita Dolzan ◽  
Viljem Kovac
Keyword(s):  
Matrix Metalloproteinases ◽  
Malignant Pleural Mesothelioma ◽  
Asbestos Exposure ◽  
Statistical Analyses ◽  
Baseline Risk ◽  
Categorical Variables ◽  
Control Group ◽  
Pleural Mesothelioma ◽  
Environment Interaction ◽  
Risk Predictors

Abstract Background Malignant mesothelioma (MM) is a rare disease, linked to asbestos exposure in more than 80% of the cases. Matrix metalloproteinases (MMPs) have been identified as modulators of the tumour microenvironment and carcinogenesis. Polymorphisms of selected MMPs have been studied as potential biomarkers of time to progression (TTP) and overall survival (OS) in MM. The aim of our study was to investigate selected MMP polymorphisms as baseline risk predictors in MM development in combination with other well known risk factors, such as asbestos exposure. Patients and methods The study included 236 patients and 161 healthy blood donors as the control group. Ten different polymorphisms in three MMP genes were genotyped using a fluorescence-based competitive allele-specific assay (KASPar): MMP2 rs243865, rs243849 and rs7201, MMP9 rs17576, rs17577, rs2250889 and rs20544, and MMP14 rs1042703, rs1042704 and rs743257. In statistical analyses continuous variables were described using median and range (25%–75%), while frequencies were used to describe categorical variables. Deviation from the Hardy-Weinberg equilibrium (HWE) was assessed using the standard chi-square test. The additive and dominant genetic models were used in statistical analyses. The association of genetic polymorphism with MM risk were examined by logistic regression to calculate odds ratios (ORs) and their 95% confidence intervals (CIs). Results Carriers of at least one polymorphic MMP2 rs243865 allele tended to have a decreased risk for MM (OR = 0.66, 95% CI = 0.44–1.00; P = 0.050). The association was more pronounced in patients with known asbestos exposure: carriers of at least one polymorphic allele had significantly lower MM risk (OR = 0.55, 95% CI = 0.35–0.86; P = 0.009). None of the other tested polymorphisms showed association with the risk of malignant pleural mesothelioma. Conclusions The MMP2 rs243865 polymorphism may have a protective role in malignant pleural mesothelioma development. This finding is even more evident in patients exposed to asbestos, implying a strong gene-environment interaction.

scholarly journals Corilagin Ameliorates Con A-Induced Hepatic Injury by Restricting M1 Macrophage Polarization

2022 ◽  
Vol 12 ◽  
Author(s):  
Fenglian Yan ◽  
Dalei Cheng ◽  
Haiyan Wang ◽  
Min Gao ◽  
Junfeng Zhang ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Hepatic Injury ◽  
Mononuclear Cells ◽  
Macrophage Polarization ◽  
Treatment Choice ◽  
Control Group ◽  
Con A ◽  
Immune Mediated ◽  
M1 Macrophage ◽  
Mitogen Activated Protein

Immune-mediated hepatic injury plays a key role in the initiation and pathogenesis of diverse liver diseases. However, treatment choice for immune-mediated hepatic injury remains limited. Corilagin, a natural ellagitannin extracted from various traditional Chinese medicines, has been demonstrated to exhibit multiple pharmacological activities, such as anti-inflammatory, anti-tumor, and hepatoprotective properties. The present study aimed to investigate the effects of corilagin on immune-mediated hepatic injury using a murine model of concanavalin A (Con A)-induced hepatitis, which is well-characterized to study acute immune-mediated hepatitis. Herein, mice were administered corilagin (25 mg/kg) intraperitoneally twice at 12 h intervals, and 1 h later, the mice were challenged with Con A (20 mg/kg body weight); serum and liver samples were collected after 12 h. The results showed that corilagin significantly increased the survival of mice and reduced serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels. In addition, corilagin markedly improved histopathological damage, hepatocyte apoptosis, and oxidative stress in the liver. The activation of M1 macrophages in the hepatic mononuclear cells was also significantly reduced compared with that in the control group. The expression of M1 macrophage-associated proinflammatory cytokines and genes, including interleukin (IL)-6, IL-12, and inducible nitric oxide synthase (iNOS), was also decreased after corilagin treatment. Finally, the results demonstrated that corilagin regulated macrophage polarization by modulating the mitogen-activated protein kinases (MAPK), nuclear factor (NF)-κB, and interferon regulatory factor (IRF) signaling pathways. Thus, the findings indicate that corilagin protects mice from Con A-induced immune-mediated hepatic injury by limiting M1 macrophage activation via the MAPK, NF-κB, and IRF signaling pathways, suggesting corilagin as a possible treatment choice for immune-mediated hepatic injury.

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