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Background Malignant pleural mesothelioma (MPM) frequently express elevated AKT/mTOR activity. Previous reports in gliomas, colon, breast and prostate cancer suggest that PTEN/PI3 K pathway may be important for the induction of PD-L1 expression. This study explored the expression of PTEN/PI3 K pathway and PD-L1 in MPM and its relationship with the patient́s prognosis Material and methods Twenty seven consecutive MPM patients were reviewed. Formalin-fixed, paraffin-embedded tissue biopsies were used for immunohistochemical analysis of PTEN/PI3 K pathway and PD-L1 Results Expression of PTEN, mTOR, pAKT, p4EBP1, peif4E, pS6 and FOXO3a was found in 88.5%, 92.3%, 78.3%, 38.5%, 100%, 52.2% and 100% of tumors and PD-L1 in 23%. We found a significant correlation between pAKT, FOXO3a and PD-L1 expression and longer overall survival (p < 0.05). We did not identify significant association between the level of PD-L1 expression and alterations in PI3 K pathway Conclusions This study shows PTEN/PI3 K pathway and PD-L1 in MPM are frequently activated. Our results suggests that there is not association between PD-L1 and the involvement of the PI3 K pathway in MPM. [ABSTRACT FROM AUTHOR]

Abstract: Background: Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm with elevated AKT/mTOR activity. We aimed to identify the expression and phosphorylation status of PTEN, PI3K and downstream signaling in MPM. Patients and methods: Thirty consecutive MPM patients were identified. Clinical data analyzed: sex, age, histology, performance status (PS), white blood count, and neutrophil–lymphocyte ratio (NLR). Paraffin-embedded biopsies were used for immunohistochemical analysis. Results: Overexpression of PTEN, pMAPK, mTOR, pAKT, 4E-BP1, p4E-BP1, eIF-4E, peIF-4E, p-S6 and FOXO3a in MPM was found in 90%, 100%, 93.3%, 80%, 100%, 43.3%, 96.7%, 100%, 63.3% and 100% of tumors respectively. There was a significant correlation between low pS6 protein expression and longer progression free survival (PFS: 7.9 vs 5.6 months; p =0.04) and overall survival (OS: 23.4 vs 5.6 months; p =0.05). Patients with concomitant low expression of pS6 and p4E-BP1 and overexpression of FOXO3a had significantly better prognosis (34.6 vs 1.9 months; p =0.004). In multivariate analysis, histology and NLR were independent prognostic factors (p =0.02 and p =0.04 respectively), but pS6 only showed a trend (p =0.8). Conclusions: This study shows PI3K pathway and downstream proteins in MPM are frequently activated and provides prognostic information. The role of PI3K pathway is worth of prospective validation in future studies on MPM. [Copyright &y& Elsevier]

Immune checkpoint inhibitors are considered standard second-line treatment in advanced non-small cell lung cancer patients. This strategy has also become standard in first-line setting for a subgroup of patients with strongly positive PD-L1 tumors; therefore, PD-L1 status might be considered a new biomarker that deserves upfront testing. New combinations of immune checkpoint inhibitors and with chemotherapy have been tested in first-line treatment. However, some questions remain unanswered such as the best treatment strategy or the real upfront efficacy of these therapeutic strategies in the whole lung cancer population. In this review we summarize the main results in the first-line setting of recent phase III trials with immune checkpoint inhibitors in advanced non-small cell lung cancer patients. [ABSTRACT FROM AUTHOR]

Background: There are few data on corticosteroids (CS)-sparing strategies for checkpoint inhibitor (ICI)-induced liver injury (ChILI)., Aim: We aimed to assess the performance of a 2-step algorithm for severe ChILI, based on ICI temporary discontinuation (step-1) and, if lack of biochemical improvement, CS based on the degree of necroinflammation at biopsy (step-2)., Methods: Prospective study that included all subjects with grade 3/4 ChILI. Peripheral extended immunophenotyping was performed. Indication for CS: severe necroinflammation; mild or moderate necroinflammation with later biochemical worsening., Results: From 111 subjects with increased transaminases (January 2020 to August 2023), 44 were diagnosed with grade 3 (N = 35) or grade 4 (N = 9) ChILI. Main reason for exclusion was alternative diagnosis. Lung cancer (13) and melanoma (12) were the most common malignancies. ICI: 23(52.3%) anti-PD1, 8(18.2%) anti-PD-L1, 3(6.8%) anti-CTLA-4, 10(22.7%) combined ICI. Liver injury pattern: hepatocellular (23,52.3%) mixed (12,27.3%) and cholestatic (9,20.5%). 14(32%) presented bilirubin >1.2 mg/dL. Overall, 30(68.2%) patients did not require CS: 22(50.0%) due to ICI discontinuation (step-1) and 8/22 (36.4%) based on the degree of necroinflammation (step-2). Biopsy mainly impacted on grade 3 ChILI, sparing CS in 8 out of 15 (53.3%) non-improvement patients after ICI discontinuation. CD8 + HLA-DR expression (p = 0.028), central memory (p = 0.046) were lower in CS-free managed subjects, but effector-memory cells (p = 0.002) were higher. Time to transaminases normalisation was shorter in those CS-free managed (overall: p < 0.001, grade 3: p < 0.001). Considering our results, a strategy based on ICI discontinuation and biopsy for grade 3 ChILI is proposed., Conclusions: An algorithm based on temporary immunotherapy discontinuation and biopsy allows CS avoidance in two thirds of cases of severe ChILI., (© 2024 The Authors. Alimentary Pharmacology & Therapeutics published by John Wiley & Sons Ltd.)

Background: ONCOS-102, an oncolytic adenovirus expressing granulocyte-macrophage colony-stimulating factor, can alter the tumor microenvironment to an immunostimulatory state. Combining ONCOS-102 with standard-of-care chemotherapy for malignant pleural mesothelioma (MPM) may improve treatment outcomes., Methods: In this open-label, randomized study, patients with unresectable MPM received intratumoral ONCOS-102 (3×10 11 virus particles on days 1, 4, 8, 36, 78, and 120) and pemetrexed plus cisplatin/carboplatin (from day 22), or pemetrexed plus cisplatin/carboplatin alone. The primary endpoint was safety. Overall survival (OS), progression-free survival, objective response rate, and tumor immunologic activation (baseline and day 36 biopsies) were also assessed., Results: In total, 31 patients (safety lead-in: n=6, randomized: n=25) were enrolled. Anemia (15.0% and 27.3%) and neutropenia (40.0% and 45.5%) were the most frequent grade ≥3 adverse events (AEs) in the ONCOS-102 (n=20) and chemotherapy-alone (n=11) cohorts. No patients discontinued ONCOS-102 due to AEs. No statistically significant difference in efficacy endpoints was observed. There was a numerical improvement in OS (30-month OS rate 34.1% vs 0; median OS 20.3 vs 13.5 months) with ONCOS-102 versus chemotherapy alone in chemotherapy-naïve patients (n=17). By day 36, ONCOS-102 was associated with increased T-cell infiltration and immune-related gene expression that was not observed in the control cohort. Substantial immune activation in the tumor microenvironment was associated with survival at month 18 in the ONCOS-102 cohort., Conclusions: ONCOS-102 plus pemetrexed and cisplatin/carboplatin was well tolerated by patients with MPM. In injected tumors, ONCOS-102 promoted a proinflammatory environment, including T-cell infiltration, which showed association with survival at month 18., Competing Interests: Competing interests: SP reports leadership/fiduciary role for Pegasys, and patent for lurbinectidin plus atezolizumab. CR reports personal payments from Bristol Meyers Squibb, MSD, and Takeda. NI reports honoraria from Amgen, Bristol Meyers Squibb, Daiichi Sankyo, Eisai, Glaxo Smith Klein, and Lilly; support for meeting attendance from Gilead, Novartis, Pfizer, PharmaMar, and Roche Genentech; and Data Safety Monitoring Board/Advisory Board participation for Transgene. SViteri reports fees from Abbvie, AstraZeneca, Bristol Meyers Squibb, Merck, Ipsen, MSD, OSE Immunotherapeutics, Puma Biotech, Roche, and Takeda. MH-J reports honoraria from AstraZeneca and support for meeting attendance from Roche and Takeda. AM-M reports honoraria from AstraZeneca/MedImmune, Bristol Myers Squibb, F. Hoffmann La Roche AG, MSD, MSD oncology, and Pfizer. AN reports consulting fees/honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Roche, Takeda; fees for expert testimony from Medsir and Oryzon; Data Safety Monitoring Board participation for Hengenix, and support for meeting attendance from Boehringer Ingelheim, Pfizer, and Roche. SC, ML and XS report no potential conflicts of interest to disclose. JZ reports research grants from AstraZeneca, Bristol Myers Squibb, and Roche; consulting fees from Bristol Myers Squibb, Novartis and Sanofi, honoraria from AstraZeneca, Bristol Myers Squibb, MSD, NanoString, Roche, and Sanofi; and support for meeting attendance from AstraZeneca, Bristol Myers Squibb, Roche, and Sanofi. SVetrhus and MJ report prior employment by Circio Holding ASA and stock in Circio Holding ASA. TBH reports employment by Circio Holding ASA and stock in Circio Holding ASA. VL reports employment with Servier, consultancy fees from Athebio AG, CatalYm, and Circio Holding ASA; and stock in Circio Holding ASA. LP-A reports grants/contracts from AstraZeneca, Bristol Meyers Squibb, MSD, and Pfizer; consulting fees from Amgen, AstraZeneca, Bayer, Bristol Meyers Squibb, GSK, Janssen, Lilly, Mirati Therapeutics, Novartis, Merck, MSD, Pfizer, Pharmamar, Roche, Daiichi Sankyo, Sanofi, Servier, and Takeda, and honoraria from AstraZeneca, Janssen, Merck, and Mirati Therapeutics., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis are the main therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) without a druggable oncogenic alteration. Nevertheless, only a portion of patients benefit from this type of treatment. Here, we assessed the value of shallow whole-genome sequencing (sWGS) on plasma samples to monitor ICI benefit. We applied sWGS on cell-free DNA (cfDNA) extracted from plasma samples of 45 patients with metastatic NSCLC treated with ICIs. Over 150 samples were obtained before ICI treatment initiation and at several time points throughout treatment. From sWGS data, we computed the tumor fraction (TFx) and somatic copy number alteration (SCNA) burden and associated them with ICI benefit and clinical features. TFx at baseline correlated with metastatic lesions at the bone and the liver, and high TFx (≥ 10%) associated with ICI benefit. Moreover, its assessment in on-treatment samples was able to better predict clinical efficacy, regardless of the TFx levels at baseline. Finally, for a subset of patients for whom SCNA burden could be computed, increased burden correlated with diminished benefit following ICI treatment. Thus, our data indicate that the analysis of cfDNA by sWGS enables the monitoring of two potential biomarkers-TFx and SCNA burden-of ICI benefit in a cost-effective manner, facilitating multiple serial-sample analyses. Larger cohorts will be needed to establish its clinical potential., (© 2023 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)