Project description:Immunotherapy has improved the prognosis of patients with advanced non-small cell lung
cancer (NSCLC), but only a small subset of patients achieved clinical benefit. The purpose of our study was to integrate multidimensional data using a machine learning method to predict the therapeutic efficacy of immune checkpoint inhibitors (ICIs) monotherapy in patients with advanced NSCLC.The authors retrospectively enrolled 112 patients with stage IIIB-IV NSCLC receiving ICIs monotherapy. The random forest (RF) algorithm was used to establish efficacy prediction models based on five different input datasets, including precontrast computed tomography (CT) radiomic data, postcontrast CT radiomic data, combination of the two CT radiomic data, clinical data, and a combination of radiomic and clinical data. The 5-fold cross-validation was used to train and test the random forest classifier. The performance of the models was assessed according to the area under the curve (AUC) in the receiver operating characteristic (ROC) curve. Among these models(RF MLP LR XGBoost), our reproduced onnx models have better performance, especially for random forest. The response variable with a value (1/0) indicates the (efficacy/inefficacy) of PD-1/PD-L1 monotherapy in patients with advanced NSCLC
2023-07-11 | BIOMD0000001074 | BioModels
Project description:Gut resistome of NSCLC patients treated with immunotherapy
Project description:Ongoing immunomodulatory strategies in tumors characterized by an overall hot immune phenotype may improve prognosis of patients with non-small cell lung cancer (NSCLC). Our objective was to develop a reliable and stable scoring system for the identification of immunologically hot NSCLC and to evaluate its association with response to immunotherapies. A Hot Oral Tumor (HOT) score was developed using data from The Cancer Genome Atlas. HOT score was computed in 82 patients with NSCLC treated with second-line immunotherapy targeting PD-1/PD-L1. High HOT score was associated with a statistically significant improved clinical outcome.
Project description:We launched an investigator-initiated, Simon’s two-stage design trial of neoadjuvant sintilimab combined with carboplatin and nab-paclitaxel (nab-PC) in early-stage EGFR-mutant NSCLC (Clinicaltrial.gov number NCT05244213). Here we report the first interim results of stage 1 cohort which met the overall primary endpoint in advance, and multi-omics profiling of neoadjuvant immunotherapy combination in early-stage EGFR-mutant patients. We performed in-depth single-cell RNA/TCR sequencing (scRNA/TCR-seq) of cells derived from 11 resected tumors as well as 34 tumors from real-world cohort which were all confirmed wild-type lung adenocarcinoma (LUAD) or adeno-squamous carcinoma (ASC) and received neoadjuvant immunochemotherapy as control. By associating the tumor microenvironment (TME) and with responses, we uncovered heterogeneous mechanisms of primary resistance, providing insights into further strategic developments of combination regimens to improve the clinical outcome of EGFR-mutant NSCLC patients.
Project description:Immunotherapy in immunologically active tumors may improve prognosis of non-small cell lung carcinomas (NSCLC). Our objective was to develop a reliable and stable scoring system for the identification of immunologically active HNSCC and to evaluate its association with response to immunotherapies. A Hot Oral Tumor (HOT) score was developed using data from The Cancer Genome Atlas in human-papillomavirus negative head and neck squamous cell carcinomas; it was computed in 92 patients with early stage NSCLC treated with surgery to evaluate the prognostic impact of the HOT score.
Project description:BACKGROUND. Precise stratification of patients with non–small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy. METHODS. We measured soluble (s) forms of the PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. Prospective biomarker finding trial (cohort A), 50 patients with pretreated NSCLC received nivolumab. In cohort B to E, retrospective observational study, soluble immune checkpoint molecules were evaluated for patients with advanced NSCLC treated with any PD-1/PD-L1 blockade (cohort B and C), cytotoxic chemotherapy (D) or targeted therapy (E). Blood samples were obtained from all patients and soluble immune checkpoint molecules were evaluated using a highly sensitive chemiluminescence-based assay. RESULTS. Nonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such correlation was not observed in patients treated with cytotoxic chemotherapy or targeted therapies. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the three soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of sPD-L1 and sCTLA-4 efficiently discriminated responsiveness among patients with immune-reactive tumors. CONCLUSION. Combinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest such a combination might provide a biomarker complementary to tPD-L1 for NSCLC patients.
Project description:Lung cancer is the second most commonly diagnosed cancer and the leading cause of cancer death worldwide, of which approximately 85% are non-small cell lung cancer (NSCLC). The overall survival (OS) of patients with advanced NSCLC was significantly prolonged with immune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) axis. For early-stage lung cancer, the 5-year survival rate for patients ranges from 80% in stage IA to 41% in stage IIIA, and many cases relapse after surgical resection. Currently, multiple clinical trials have manifested the encouraging efficacy of neoadjuvant immunotherapy in stage I-IIIA resectable NSCLC. However, the effect of immunotherapy in ultra early-stage NSCLC patients with micro-invasive or even pre-invasive lesions remains unclear. In this study, we aimed to evaluate the activity and safety of sintilimab on high-risk ground glass opacity lesions in multiple primary lung cancer patients.
Project description:Purpose: The major aim of this study was to investigate the role of DNA methylation (referred to as methylation) on microRNA (miRNA) silencing in non-small cell lung cancers (NSCLC). Experimental Design: We performed microarray expression analyses of 856 miRNAs in NSCLC A549 cells before and after treatment with the DNA methyltransferase inhibitor 5-aza-2´-deoxycytidine (Aza-dC) and with a combination of Aza-dC and the histone deacetylase inhibitor trichostatin A. MiRNA methylation was determined in 11 NSCLC cell lines and in primary tumors and corresponding non-malignant lung tissue samples of 101 stage I-III NSCLC patients. Results: By comparing microarray data of untreated and drug treated A549 cells, we identified 33 miRNAs whose expression was upregulated after drug treatment and which are associated with a CpG island. Thirty (91%) of these miRNAs were found to be methylated in at least 1 of 11 NSCLC cell lines analysed. Moreover, miR-9-3 and miR-193a were found to be tumor-specifically methylated in NSCLC patients. We observed a shorter disease-free survival of miR-9-3 methylated lung squamous cell carcinoma (LSCC) patients compared to miR-9-3 unmethylated LSCC patients by multivariate analysis (HR = 3.8, 95% CI = 1.3 to 11.2, p = 0.017) and a shorter overall survival of miR-9-3 methylated LSCC patients compared to miR-9-3 unmethylated LSCC patients by univariate analysis (p = 0.013). Conclusions: Overall, our results suggest that methylation is an important mechanism for inactivation of certain miRNAs in NSCLCs and that miR-9-3 methylation may serve as a prognostic parameter in LSCC patients. MiRNA expression (LC Sciences, mirBASE12) was analyzed before and after treatment of A549 cells with 5-aza-2´-deoxycytidine (Aza-dC) and a combination of Aza-dC and trichostatin A (TSA). Experiments were performed in duplicates.