Pre-clinical Efficacy and Safety Pharmacology of PEGylated Recombinant Human Endostatin.

INTRODUCTION: This study aimed to outline the pre-clinical efficacy and safety pharmacology of PEGylated recombinant human endostatin (M2ES) according to the requirements of new drug application. METHODS: The purity of M2ES was evaluated by using silver staining. Transwell migration assay was applied to detect the bioactivity of M2ES in vitro. The antitumor efficacy of M2ES was evaluated in an athymic nude mouse xenograft model of pancreatic cancer (Panc-1) and gastric cancer (MNK45). BALB/C mice were treated with different doses of M2ES (6, 12 and 24 mg/kg) intravenously, both autonomic activity and cooperative sleep were monitored before and after drug administration. RESULTS: The apparent molecular weight of M2ES was about 50 kDa, and the purity was greater than 98%. Compared with the control group, M2ES significantly inhibits human micro-vascular endothelial cells (HMECs) migration in vitro. Notably, weekly administration of M2ES showed a significant antitumor efficacy when compared with the control group. Treatment of M2ES (24mg/kg or below) showed no obvious effect on both autonomic activity and hypnosis. CONCLUSION: On the basis of the pre-clinical efficacy and safety pharmacology data of M2ES, M2ES can be authorized to carry out further clinical studies.

Identification of lung adenocarcinoma subtypes and predictive signature for prognosis, immune features, and immunotherapy based on immune checkpoint genes.

Background: Lung adenocarcinoma (LUAD) is the most common variant of non-small cell lung cancer (NSCLC) across the world. Recently, the rapid development of immunotherapy has brought a new dawn for LUAD patients. Closely related to the tumor immune microenvironment and immune cell functions, more and more new immune checkpoints have been discovered, and various cancer treatment studies targeting these novel immune checkpoints are currently in full swing. However, studies on the phenotype and clinical significance of novel immune checkpoints in LUAD are still limited, and only a minority of patients with LUAD can benefit from immunotherapy. Methods: The LUAD datasets were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, and the immune checkpoints score of each sample were calculated based on the expression of the 82 immune checkpoints-related genes (ICGs). The weighted gene co-expression network analysis (WGCNA) was used to obtain the gene modules closely related to the score and two different LUAD clusters were identified based on these module genes by the Non-negative Matrix Factorization (NMF) Algorithm. The differentially expressed genes between the two clusters were further used to construct a predictive signature for prognosis, immune features, and the response to immunotherapy for LUAD patients through a series of regression analyses. Results: A new immune checkpoints-related signature was finally established according to the expression of 7 genes (FCER2, CD200R1, RHOV, TNNT2, WT1, AHSG, and KRTAP5-8). This signature can stratify patients into high-risk and low-risk groups with different survival outcomes and sensitivity to immunotherapy, and the signature has been well validated in different clinical subgroups and validation cohorts. Conclusion: We constructed a novel immune checkpoints-related LUAD risk assessment system, which has a good predictive ability and significance for guiding immunotherapy. We believe that these findings will not only aid in the clinical management of LUAD patients but also provide some insights into screening appropriate patients for immunotherapy.

Efficacy of immune-checkpoint inhibitors in PD-L1 selected or unselected patients vs. control group in patients with advanced or metastatic urothelial carcinoma.

Most patients with advanced or metastatic urothelial carcinoma do not benefit significantly from Immune checkpoint inhibitors (ICIs) use. A systematic review and meta-analysis of randomized controlled trials to assess the efficacy and activity of ICIs, in terms of Overall Survival (OS), Progression-free survival (PFS), and Objective Response Rate (ORR). We systematically searched for articles from PubMed, Cochrane Library, Embase, and Web of science from their inception to December 1, 2020 with no language restrictions. The search was performed to identify all clinical trials (phase I, phase II, phase III) of ICIs for treating urothelial carcinoma. The endpoints of the meta-analysis were OS, PFS, and ORR, compared unselected patients and in the subgroup of patients characterized by high expression of PD-L1 (PD-L1 selected patients). Sixteen studies comprising 5559 patients were identified, of which data for OS comparison were available from 4 RCTs (2342 patients), two studies for PFS (649 patients), and four RCTs were eligible for ORR analysis (2921 patients). Both pembrolizumab and atezolizumab have showed to improve OS compared to chemotherapy in unselected patients (HR 0.86, 95% CI 0.80-0.93, P = .0001, I2 = 60%), while the difference was not significant in PD-L1 selected patients (HR 0.91, 95% CI 0.77-1.07, P = .23, I2 = 0%). PFS difference was not observed in neither unselected population nor PD-L1 selected patients, the pooled HR of PFS for immunotherapy compared to control treatment was 1.05 (95% CI 0.74-1.49, P = .79, I2 = 85%) and 0.84 (95% CI 0.68-1.03, P = .09, I2 = 0%, respectively. Similar result was observed in ORR, the pooled HR of ORR for immunotherapy compared to control treatment was 1.45 (95% CI 0.53-3.98, P = .47, I2 = 95%) and 2.19 (95% CI 0.79-6.08, P = .13, I2 = 83%), respectively. Immunotherapy could significantly improve survival advantage in unselected patients but not in PD-L1 selected population, indicating that PD-L1 expression may not be a reliable marker in previously platinum-treated patients.