Citations

Abstract Purpose: The aim of the study was to determine safety, antitumor activity, and pharmacodynamic profile of mogamulizumab, an anti-CCR4 monoclonal antibody targeting effector regulatory T cells (Treg) in combination with the checkpoint inhibitor nivolumab in patients with locally advanced or metastatic solid tumors. Patients and Methods: This was a multicenter, dose-finding (phase I), and dose expansion (phase II) study (NCT02705105) in patients with locally advanced or metastatic solid tumors. There were no dose-limiting toxicities in phase I with mogamulizumab 1 mg/kg every week for cycle 1 followed by 1 mg/kg every 2 weeks plus nivolumab 240 mg every 2 weeks intravenously, and cohort expansion occurred at this dose level. Results: All 114 patients treated with mogamulizumab 1 mg/kg plus nivolumab 240 mg in phases I (n = 4) and II (n = 110) were assessed for safety and efficacy. Mogamulizumab plus nivolumab showed acceptable safety and tolerability. Objective response rate was 10.5% [95% confidence interval (CI), 5.6–17.7; 3 complete and 9 partial responses]. Disease control rate was 36.8%. Median duration of response was 14.4 months. Median progression-free survival was 2.6 (95% CI, 2.3–3.1) months, and median overall survival was 9.5 (95% CI, 5.9–13.5) months. Conclusions: Combination of mogamulizumab with nivolumab for treatment of patients with locally advanced or metastatic solid tumors did not result in enhanced efficacy. Tolerability of mogamulizumab 1 mg/kg plus nivolumab 240 mg was acceptable.

Significance Glucocorticoids are widely prescribed antiinflammatory drugs that suppress inflammatory gene expression through activation of the glucocorticoid receptor (GR); however, the mechanisms of GR-mediated repression are not fully understood. We show here that bromodomain containing 9 (BRD9), a component of the SWI/SNF chromatin remodeling complex, modulates GR activity in bone marrow-derived macrophages. Loss of BRD9 activity in macrophages attenuated the response to liposaccharides and interferon inflammatory stimuli. Notably, BRD9 inhibition synergized with the synthetic glucocorticoid dexamethasone to suppress the inflammatory response in macrophages. Our data support a model in which BRD9 restricts GR binding at a subset of inflammatory related genes, and suggests that BRD9 inhibitors may increase the efficacy of glucocorticoids.

Eosinophils protect against liver injury during orthotopic liver transplantation and other conditions of hepatic ischemia-reperfusion injury in mice.

AbstractBackgroundEnergy balance-related biomarkers are associated with risk and prognosis of various malignancies. Their relationship to survival in metastatic colorectal cancer (mCRC) requires further study.MethodsBaseline plasma insulin-like growth factor (IGF)-1, IGF-binding protein (IGFBP)-3, IGFBP-7, C-peptide, and adiponectin were measured at time of trial registration in a prospective cohort of patients with mCRC participating in a National Cancer Institute–sponsored trial of first-line systemic therapy. We used Cox proportional hazards regression to adjust for confounders and examine associations of each biomarker with overall survival (OS) and progression-free survival (PFS). P values are 2-sided.ResultsMedian follow-up for 1086 patients was 6.2 years. Compared with patients in the lowest IGFBP-3 quintile, patients in the highest IGFBP-3 quintile experienced an adjusted hazard ratio (HR) for OS of 0.57 (95% confidence interval [CI] = 0.42 to 0.78; Pnonlinearity < .001) and for PFS of 0.61 (95% CI = 0.45 to 0.82; Ptrend = .003). Compared with patients in the lowest IGFBP-7 quintile, patients in the highest IGFBP-7 quintile experienced an adjusted hazard ratio for OS of 1.60 (95% CI = 1.30 to 1.97; Ptrend < .001) and for PFS of 1.38 (95% CI = 1.13 to 1.69; Ptrend < .001). Plasma C-peptide and IGF-1 were not associated with patient outcomes. Adiponectin was not associated with OS; there was a nonlinear U-shaped association between adiponectin and PFS (Pnonlinearity = .03).ConclusionsAmong patients with mCRC, high plasma IGFBP-3 and low IGFBP-7 were associated with longer OS and PFS. Extreme levels of adiponectin were associated with shorter PFS. These findings suggest potential avenues for prognostic and therapeutic innovation.

We identified a potentially novel homozygous duplication involving the promoter region and exons 1–4 of the gene encoding type 2 cardiac ryanodine receptor ( RYR2 ) that is responsible for highly penetrant, exertion-related sudden deaths/cardiac arrests in the Amish community without an overt phenotype to suggest RYR2- mediated catecholaminergic polymorphic ventricular tachycardia (CPVT). Homozygous RYR2 duplication (RYR2-DUP) induced pluripotent stem cell cardiomyocytes (iPSC-CMs) were generated from 2 unrelated patients. There was no difference in baseline Ca 2+ handling measurements between WT-iPSC-CM and RYR2-DUP-iPSC-CM lines. However, compared with WT-iPSC-CMs, both patient lines demonstrated a dramatic reduction in caffeine-stimulated and isoproterenol-stimulated (ISO-stimulated) Ca 2+ transient amplitude, suggesting RyR2 loss of function. There was a greater than 50% reduction in RYR2 transcript/RyR2 protein expression in both patient iPSC-CMs compared with WT. Delayed afterdepolarization was observed in the RYR2-DUP-iPSC-CMs but not in the WT-iPSC-CMs. Compared with WT-iPSC-CMs, there was significantly elevated arrhythmic activity in the RYR2-DUP-iPSC-CMs in response to ISO. Nadolol, propranolol, and flecainide reduced erratic activity by 8.5-fold, 6.8-fold, and 2.4-fold, respectively, from ISO challenge. Unlike the gain-of-function mechanism observed in RYR2- mediated CPVT, the homozygous multiexon duplication precipitated a dramatic reduction in RYR2 transcription and RyR2 protein translation, a loss of function in calcium handling, and a calcium-induced calcium release apparatus that is insensitive to catecholamines and caffeine.

Abstract Background Dysphagia is the main symptom of adult eosinophilic esophagitis (EoE). We describe a novel syndrome, referred to as “food‐induced immediate response of the esophagus” (FIRE), observed in EoE patients. Methods Food‐induced immediate response of the esophagus is an unpleasant/painful sensation, unrelated to dysphagia, occurring immediately after esophageal contact with specific foods. Eosinophilic esophagitis experts were surveyed to estimate the prevalence of FIRE, characterize symptoms, and identify food triggers. We also surveyed a large group of EoE patients enrolled in the Swiss EoE Cohort Study for FIRE. Results Response rates were 82% (47/57) for the expert and 65% (239/368) for the patient survey, respectively. Almost, 90% of EoE experts had observed the FIRE symptom complex in their patients. Forty percent of EoE patients reported experiencing FIRE, more commonly in patients who developed EoE symptoms at a younger age (mean age of 46.4 years vs 54.1 years without FIRE; P < .01) and in those with high allergic comorbidity. Food‐induced immediate response of the esophagus symptoms included narrowing, burning, choking, and pressure in the esophagus appearing within 5 minutes of ingesting a provoking food that lasted less than 2 hours. Symptom severity rated a median 7 points on a visual analogue scale from 1 to 10. Fresh fruits/vegetables and wine were the most frequent triggers. Endoscopic food removal was significantly more commonly reported in male patients with vs without FIRE (44.3% vs 27.6%; P = .03). Conclusions Food‐induced immediate response of the esophagus is a novel syndrome frequently reported in EoE patients, characterized by an intense, unpleasant/painful sensation occurring rapidly and reproducibly in 40% of surveyed EoE patients after esophageal contact with specific foods.

8010 Background: In patients (pts) with metastatic melanoma (MM), tumor angiogenesis has been associated with tumor progression and survival (Ugurel et al, JCO 19:577). Microtubule and cyclooxygenase (COX)-2 inhibitors, both alone and in combination, have been shown to have inhibitory effects on endothelial cells and tumor angiogenesis both in vitro and in vivo (Merchan et al, Int J Ca 113:490. Jones et al, Nat Med 5:1418). We tested the safety and efficacy of a regimen involving low dose, continuous infusion (CIV) paclitaxel and oral celecoxib in pts with MM. Methods: Pts received paclitaxel 10mg/m2 for 96 hours weekly by CIV and Celecoxib 400 mg po/bid. Systemic tumor response was assessed at 6 wk intervals (1 cycle (C)). Pts without unacceptable toxicity or clinically significant disease progression (PD) received additional cycles. Pts exhibiting PD after C 2 relative to end of C 1 were removed from study. Pts on anticoagulants, with recent MI or untreated brain metastases were ineligible. Results: 20 pts (12 M/ 8 F), median age 55 (range 44–65), ECOG PS 0/1/2 (5/13/2), M1a/M1b/M1c: 1/1/18 (90%), and prior systemic therapy regimens 0/1/2/3+: 1/7/5/7 were enrolled in the protocol. Sites of systemic disease included: lung (13 pts), LN (14), soft tissue (13), liver (9), bone (4), brain (6), other (11). 3 pts came of study prior to treatment with rapid disease progression. Treatment related grade 3–4 toxicities included line related (LR) bacteremia (3 pts), LR DVT (3 pts), LR PE (3). There were no grade 3–4 toxicities attributed to paclitaxel or celecoxib. No pt exhibited a major tumor response; 6/20 (30%) pts had stable disease for 17, 18, 18, 18+, 30+, 60 wks. Median TTP was 6 wks (range 3- 60); median overall survival was 6 months (range 1–29). Conclusions: Low-dose, CIV paclitaxel and oral celecoxib leads to disease stabilization in a significant portion of previously treated pts with MM. This suggests a role for combination anti-angiogenic therapy in MM. The incidence of LR toxicities indicates that alternative microtubule inhibitors, such as oral taxanes, should be considered in combination with COX-2 inhibitors for future studies. Results of biomarker studies will be presented at the meeting. Supported by Pfizer Inc. and NIH R21 CA097730. [Table: see text]

Objective To evaluate patient‐reported outcome (PRO) data from the IMmotion150 study. The phase 2 IMmotion150 study showed improved progression‐free survival with atezolizumab plus bevacizumab vs sunitinib in patients with programmed death‐ligand 1 (PD‐L1)+ tumours and suggested activity of atezolizumab monotherapy in previously untreated metastatic renal cell carcinoma (mRCC). Patients and methods Patients with previously untreated mRCC were randomised to atezolizumab 1200 mg intravenously (i.v.) every 3 weeks ( n = 103), the atezolizumab regimen plus bevacizumab 15 mg/kg i.v. every 3 weeks ( n = 101), or sunitinib 50 mg orally daily (4 weeks on, 2 weeks off; n = 101). The MD Anderson Symptom Inventory (MDASI) and Brief Fatigue Inventory (BFI) were administered on days 1 and 22 of each 6‐week cycle. Time to deterioration (TTD), change from baseline in MDASI core and RCC symptom severity, interference with daily life, and BFI fatigue severity and interference scores were reported for all comers. The TTD was the first ≥2‐point score increase over baseline. Absolute effect size ≥0.2 suggested a clinically important difference with checkpoint inhibitor therapy vs sunitinib. Results Completion rates were >90% at baseline and ≥80% at most visits. Delayed TTD in core and RCC symptoms, symptom interference, fatigue, and fatigue‐related interference was observed with atezolizumab (both alone and in combination) vs sunitinib. Improved TTD (hazard ratio [HR], 95% confidence interval [CI]) was more pronounced with atezolizumab monotherapy: core symptoms, 0.39 (0.22–0.71); RCC symptoms, 0.22 (0.12–0.41); and symptom interference, 0.36 (0.22–0.58). Change from baseline by visit, evaluated by the MDASI, also showed a trend favouring atezolizumab monotherapy vs sunitinib. Small sample sizes may have limited the ability to draw definitive conclusions. Conclusion PROs suggested that atezolizumab alone or with bevacizumab maintained daily function compared with sunitinib. Notably, symptoms were least severe with atezolizumab alone vs sunitinib (IMmotion150; ClinicalTrials.gov Identifier: NCT01984242).