ABSTRACT
BACKGROUND: Nivolumab is a programmed cell death 1 (PD-1) receptor inhibitor antibody that enhances immune system antitumor activity. It is associated with longer overall survival (OS) than the standard treatment of docetaxel in patients with previously treated advanced squamous (SQ) and non-squamous (non-SQ) non-small cell lung cancer (NSCLC). We previously conducted two phase II studies of nivolumab in Japanese patients with SQ (ONO-4538-05) and non-SQ (ONO-4538-06) NSCLC, showing overall response rates (ORRs) (95% CI) of 25.7% (14.2-42.1) and 22.4% (14.5-32.9), respectively, with acceptable toxicity. In this analysis, we more precisely estimated the long-term safety and efficacy in patients with SQ and non-SQ NSCLC by pooling data from these two trials. METHODS: SQ (N = 35) and non-SQ (N = 76) NSCLC patients received nivolumab (3 mg/kg, every 2 weeks) until progression or discontinuation. OS was estimated using the Kaplan-Meier method. A pooled analysis of SQ and non-SQ patients was also performed. RESULTS: In SQ NSCLC patients, the median OS (95% CI) was 16.3 months (12.4-25.2), and the estimated 1-year, 2-year, and 3-year survival rates were 71.4% (53.4-83.5), 37.1% (21.6-52.7), and 20.0% (8.8-34.4), respectively. In non-SQ NSCLC patients, median OS was 17.1 months (13.3-23.0), and the estimated 1-, 2-, and 3-year survival rates were 68.0% (56.2-77.3), 37.4% (26.5-48.1), and 31.9% (21.7-42.5), respectively. When SQ NSCLC and non-SQ NSCLC data were pooled, the median OS was 17.1 months (14.2-20.6), and the estimated 1-, 2-, and 3-year survival rates were 69.1% (59.6-76.8), 37.3% (28.3-46.2), and 28.1% (20.0-36.7), respectively. Twenty (76.9%) of 26 responders lived for 3 or more years. Nivolumab was well tolerated and no new safety signals were found. CONCLUSION: Treatment with nivolumab improved long-term survival and was well tolerated in patients with SQ and non-SQ NSCLC. TRIAL REGISTRATION: JapicCTI-132072; JapicCTI-132073.
Subject(s)
Antineoplastic Agents, Immunological/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Non-Small-Cell Lung/pathology , Lung Neoplasms/drug therapy , Lung Neoplasms/pathology , Nivolumab/therapeutic use , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Immunological/administration & dosage , Antineoplastic Agents, Immunological/adverse effects , Biomarkers, Tumor , Carcinoma, Non-Small-Cell Lung/etiology , Carcinoma, Non-Small-Cell Lung/mortality , Clinical Trials, Phase II as Topic , Female , Humans , Japan , Kaplan-Meier Estimate , Lung Neoplasms/etiology , Lung Neoplasms/mortality , Male , Middle Aged , Molecular Targeted Therapy , Neoplasm Metastasis , Neoplasm Staging , Nivolumab/administration & dosage , Nivolumab/adverse effects , Treatment OutcomeABSTRACT
Limited treatment options are available for stage IIIB/IV non-small cell lung cancer (NSCLC). Nivolumab, a programmed cell death-1 immune checkpoint inhibitor antibody, has been shown to be effective for the treatment of NSCLC. The present study investigated the effectiveness and safety of nivolumab in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. In this multicenter phase II study, patients were treated with nivolumab (3 mg/kg, i.v.) every 2 weeks until progressive disease or unacceptable toxicity was seen. Primary endpoint was overall response rate (ORR) assessed by independent radiology review committee (IRC) and secondary endpoints included a study site-assessed ORR, overall survival (OS), progression-free survival (PFS), duration of response, time to response, best overall response (BOR), and safety. The study included 35 patients from 17 sites in Japan. Patients had IRC-assessed ORR of 25.7% (95% CI 14.2, 42.1) and the study site-assessed ORR was 20.0% (95% CI 10.0, 35.9). Median OS, median time to response and median PFS were 16.3 (95% CI 12.4-25.4), 2.7 (range 1.2-5.5) and 4.2 (95% CI 1.4-7.1) months, respectively. The IRC-assessed BOR was partial response, stable disease, and progressive disease for 25.7%, 28.6%, and 45.7% of patients, respectively. Treatment-related adverse events were reported in 24 patients (68.6%), most of which resolved with appropriate treatment including steroid therapy or discontinuation of nivolumab. Nivolumab was effective and well tolerated in Japanese patients with advanced or recurrent squamous NSCLC that progressed after platinum-containing chemotherapy. CLINICAL TRIAL REGISTRATION NUMBER: JapicCTI-132072.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/adverse effects , Antineoplastic Agents/therapeutic use , Carcinoma, Non-Small-Cell Lung/drug therapy , Carcinoma, Squamous Cell/drug therapy , Lung Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Aged , Asian People , Disease-Free Survival , Female , Humans , Male , NivolumabABSTRACT
OBJECTIVE: Nivolumab is a fully human IgG4 programmed cell death 1 immune checkpoint inhibitor monoclonal antibody approved for the treatment of non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of nivolumab in Japanese patients with advanced or recurrent non-squamous NSCLC. METHODS: In this multicentre phase II study, patients with advanced or recurrent non-squamous NSCLC, which had progressed after platinum-containing chemotherapy, were treated with nivolumab 3â mg/kg, intravenously every 2â weeks until progressive disease or unacceptable toxicity was observed. The primary end point was independent radiology review committee (IRC) assessed overall response rate (ORR) and the secondary endpoints included ORR (investigator assessed), progression-free survival (PFS), overall survival (OS), duration of response, time to response, best overall response, and safety. RESULTS: 76 patients were enrolled across 19 sites in Japan. The ORR (IRC assessed) was 22.4% (95% CI 14.5% to 32.9%). The median PFS and OS were 2.8â months (95% CI 1.4 to 3.4) and 17.1â months (95% CI 13.3 to 23.0), respectively. The OS rate at 1â year was 68.0% (95% CI 56.2% to 77.3%). Current/former smokers were more responsive to treatment than non-smokers (ORR 29.1% vs 4.8%). Patients with epidermal growth factor receptor (EGFR) mutation wild type/unknown showed higher ORR compared with EGFR mutation-positive patients (ORR 28.6% vs 5.0%) and programmed cell death ligand-1 (PD-L1) expression was likely associated with higher ORR, longer PFS and OS. Treatment-related adverse events of grade 3 or higher were reported in 17 patients; these events resolved or were resolving with appropriate treatment including steroid therapy or discontinuation of nivolumab. CONCLUSIONS: Nivolumab was well tolerated and showed clinical efficacy in Japanese patients with non-squamous NSCLC progressed after platinum-containing chemotherapy, especially in those with a history of smoking, wild type/unknown EGFR mutation status or positive PD-L1 expression. TRIAL REGISTRATION NUMBER: JapicCTI-132073.
ABSTRACT
Zinc finger protein ZPR1 (ZPR1) binds to eukaryotic translation elongation factor 1alpha (eEF1alpha) in response to growth stimuli, and is also involved in transcription and cell cycle regulation. In this study, we characterized the interaction of ZPR1 and eEF1alpha and generated a ZPR1 mutant that constitutively interacted with eEF1alpha. ZPR1-DeltaA (Delta193-246) bound to eEF1alpha independently of Zn(2+) in vivo. This study indicates that ZPR1-DeltaA (Delta193-246) is a useful tool to provide structural insights into ZPR1 and to investigate the biological significance of the interaction between ZPR1 and eEF1alpha.
Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Mutant Proteins/genetics , Mutant Proteins/metabolism , Mutation , Peptide Elongation Factor 1/metabolism , Animals , Cell Line , Humans , Intracellular Signaling Peptides and Proteins , Mice , Protein BindingABSTRACT
A differential display was performed to analyze differential gene expression in the brains of mice in association with dietary high beef-tallow. Consumption of a high beef-tallow diet downregulated the expression of ADP-ribosylation factor-like protein 8B (Arl8B) mRNA in the brain. Arl8B mRNA was widely expressed in the mouse brain, including primary neuronal cells. The current study indicates that green fluorescent protein-fused Arl8B protein accumulated at the growth cones in primary neuronal cells, and that protrusions of human embryonic kidney 293 (HEK293) cells were significantly elongated by overexpression of Arl8B, suggesting an important role of Arl8B in neurite formation.
Subject(s)
ADP-Ribosylation Factors/biosynthesis , Brain/metabolism , Dietary Fats/administration & dosage , Animals , Cells, Cultured , Down-Regulation , Gene Expression Profiling , Growth Cones/physiology , Humans , Male , Mice , Mice, Inbred ICR , Neurons/metabolism , RNA, Messenger/biosynthesis , Recombinant Fusion Proteins/biosynthesis , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
A differential display was performed to analyze differential gene expression in the brain of mice in association with dietary high beef tallow. Consumption of a high beef tallow diet up-regulated the expression of zinc finger protein ZPR1 mRNA in the brain. Expression of ZPR1 mRNA in the cerebellum and hippocampus was elevated in response to the high beef tallow diet. The increased ZPR1 expression in the neuronal, Neuro-2A cells, caused a significant increase in H(2)O(2)-induced cell death. These results suggest that a high beef tallow diet up-regulates ZPR1 mRNA expression in the brain and might increase the vulnerability to oxidative stress.
Subject(s)
Brain/metabolism , Carrier Proteins/genetics , Dietary Fats/pharmacology , Up-Regulation/drug effects , Animals , Antibodies , Brain/cytology , Carrier Proteins/metabolism , Cell Death/drug effects , Cell Survival/drug effects , Cells, Cultured , Dietary Fats/administration & dosage , Fats/administration & dosage , Fats/pharmacology , Gene Expression Profiling , Gene Expression Regulation , Hydrogen Peroxide/pharmacology , Intracellular Signaling Peptides and Proteins , Male , Mice , Mice, Inbred ICR , RNA, Messenger/genetics , RNA, Messenger/metabolism , Transfection , Up-Regulation/geneticsABSTRACT
Previous studies have suggested that docosahexaenoic acid (DHA), contained in fish oil, prevents brain disease. In the current study, the effect of fish oil feeding on gene expression in the brain was investigated by suppression subtractive hybridization. We found that pyruvate dehydrogenase E1 alpha (PDHE1alpha) mRNA expression is down-regulated by fish oil feeding. We examined whether the expression of PDHE1alpha mRNA is altered by DHA treatment in differentiated PC12 cells. PDHE1alpha mRNA was reduced by supplementation of DHA with a significant decrease in cellular ATP level. These results indicate that fish oil feeding might modulate energy metabolism in the brain.
