Stabilized tilted-octahedra halide perovskites inhibit local formation of performance-limiting phases.

Efforts to stabilize photoactive formamidinium (FA)–based halide perovskites for perovskite photovoltaics have focused on the growth of cubic formamidinium lead iodide (α-FAPbI3) phases by empirically alloying with cesium, methylammonium (MA) cations, or both. We show that such stabilized FA-rich perovskites are noncubic and exhibit ~2° octahedral tilting at room temperature. This tilting, resolvable only with the use of local nanostructure characterization techniques, imparts phase stability by frustrating transitions from photoactive to hexagonal phases. Although the bulk phase appears stable when examined macroscopically, heterogeneous cation distributions allow microscopically unstable regions to form; we found that these transitioned to hexagonal polytypes, leading to local trap-assisted performance losses and photoinstabilities. Using surface-bound ethylenediaminetetraacetic acid, we engineered an octahedral tilt into pure α-FAPbI3 thin films without any cation alloying. The templated photoactive FAPbI3 film was extremely stable against thermal, environmental, and light stressors

RPC4046, a Monoclonal Antibody Against IL13, Reduces Histologic and Endoscopic Activity in Patients With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, esophageal, type 2 inflammatory response associated with increased serum levels of interleukin 13 (IL13), which might contribute to its pathogenesis. RPC4046, a recombinant humanized monoclonal antibody against IL13, prevents its binding to the receptor subunits IL13RA1 and IL13RA2. We performed a phase 2 trial to evaluate the efficacy and safety of RPC4046 in patients with EoE. We performed a multicenter, double-blind trial of 99 adults with active EoE randomly assigned (1:1:1) to groups given RPC4046 (180 or 360 mg) or placebo once weekly for 16 weeks, from September 2014 through December 2015. Patients were seen at day 1 (baseline) and weeks 2, 4, 8, 12, and 16. They underwent esophagogastroduodenoscopy and biopsies were collected at baseline and week 16. Patients completed a daily dysphagia symptom diary through week 16 and patient-reported outcome data were collected. The primary outcome was change in mean esophageal eosinophil count in the 5 high-power fields (hpfs) with the highest level of inflammation. At week 16, mean changes in esophageal eosinophil count per hpf were a reduction of 94.8 ± 67.3 in patients who received 180 mg RPC4046 (P < .0001) and a reduction of 99.9 ± 79.5 in patients who received 360 mg RPC4046 (P < .0001) compared with a reduction of 4.4 ± 59.9 in patients who received placebo. The 360-mg RPC4046 group, compared with the placebo group, showed significant reductions in validated endoscopic severity score at all esophageal locations (P < .0001), validated histologic grade and stage scores (both P < .0001), and clinician's global assessment of disease severity (P = .0352); they had a numerical reduction in scores from the dysphagia symptom diary (P = .0733). Significant reductions in esophageal eosinophil counts and histologic and endoscopic features were observed in patients with steroid-refractory EoE who received RPC4046. The most common adverse events were headache and upper respiratory tract infection. In a phase 2 trial of patients with EoE, we found RPC4046 (a monoclonal antibody against IL13) to reduce histologic and endoscopic features compared with placebo. RPC4046 was well tolerated. ClinicalTrials.gov no: NCT02098473

Role of Vγ9vδ2 T lymphocytes in infectious diseases

The T cell receptor Vγ9Vδ2 T cells bridge innate and adaptive antimicrobial immunity in primates. These Vγ9Vδ2 T cells respond to phosphoantigens (pAgs) present in microbial or eukaryotic cells in a butyrophilin 3A1 (BTN3) and butyrophilin 2A1 (BTN2A1) dependent manner. In humans, the rapid expansion of circulating Vγ9Vδ2 T lymphocytes during several infections as well as their localization at the site of active disease demonstrates their important role in the immune response to infection. However, Vγ9Vδ2 T cell deficiencies have been observed in some infectious diseases such as active tuberculosis and chronic viral infections. In this review, we are providing an overview of the mechanisms of Vγ9Vδ2 T cell-mediated antimicrobial immunity. These cells kill infected cells mainly by releasing lytic mediators and pro-inflammatory cytokines and inducing target cell apoptosis. In addition, the release of chemokines and cytokines allows the recruitment and activation of immune cells, promoting the initiation of the adaptive immune response. Finaly, we also describe potential new therapeutic tools of Vγ9Vδ2 T cell-based immunotherapy that could be applied to emerging infections

Suivi traumatologique d'une équipe de la ligue nationale de rugby, saison 1998-1999

Background: Fibrocaps, a ready-to-use, dry-powder fibrin sealant containing human plasma-derived thrombin and fibrinogen, is being developed as an adjunct for surgical hemostasis. Materials and methods: Safety and efficacy of Fibrocaps applied directly or by spray device, in combination with gelatin sponge, was compared with that of gelatin sponge-alone in two randomized, single-blind controlled trials: FC-002 US (United States) and FC-002 NL (the Netherlands). A total of 126 adult patients were randomized (Fibrocaps: n = 47 [FC-002 US], n = 39 [FC-002 NL]; gelatin sponge alone: n = 23 [FC-002 US], n = 17 [FC-002 NL). One bleeding site was treated during a surgical procedure (n = 125). Time to hemostasis (primary end point) was measured, with a 28-d safety follow-up. Four surgical indications included hepatic resection (n = 58), spinal procedures (n = 37), peripheral vascular procedures (n = 30), and soft tissue dissection (n = 1). Results: Mean (standard deviation) time to hemostasis was significantly shorter after Fibrocaps treatment than after gelatin sponge alone (FC-002 US: 1.9 [1.3] versus 4.8 min [3.1], P <0.001; FC-002 NL: 2.2 [1.3] versus 4.4 min [3.1], P = 0.004). The incidence of hemostasis was greater after Fibrocaps compared with that of gelatin sponge alone within 3 min (FC-002 US: 83% versus 35%, P <0.001; FC-002 NL: 77% versus 53%, P = 0.11), 5 min (94% versus 61%, P = 0.001; 95% versus 71%, P = 0.022), and 10 min (100% versus 78%, P = 0.003; 100% versus 82%, P = 0.025). Adverse events were consistent with surgical procedures performed and patients' underlying diseases and generally similar between treatment arms; most were mild or moderate in severity. Non-neutralizing antithrombin antibodies were detected in 5% of Fibrocaps-treated patients on day 29. Conclusions: Fibrocaps had good safety and efficacy profiles, supporting continuing clinical development as a novel fibrin sealant. (C) 2015 Elsevier Inc. All rights reserved

Abstract CT034: Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study

International audienceAbstract Background: Gamma9 Delta2 (γ9δ2) T cells function at the crossroad of innate and adaptive immunity with important roles in immune responses against pathogens and carcinogenesis, making them an attractive target for cancer immunotherapy. Butyrophilin (BTN) 3A (CD277) is an immune checkpoint molecule expressed on tumors and cells of the immune system that is required for γ9δ2 T cell activation. These observations led to the design and development of ICT01, a humanized, monoclonal antibody that binds the extracellular domain of all 3 isoforms of BTN3A1/A2/A3 and induces pAg-independent γ9δ2 T cell activation and killing of multiple tumors in nonclinical settings. Methods: EVICTION (www.clinicaltrials.gov NCT04243499; EudraCT Number: 2019-003847-31) is a first-in-human, open-label clinical study to assess the safety, tolerability, and activity of a range of IV doses of ICT01 as monotherapy and in combination with pembrolizumab, in patients with advanced-stage, relapsed/refractory cancer. Following Regulatory and Ethics Committee approvals, the study is being conducted at cancer centers in France, Belgium, Spain, Germany, the UK and USA. Following signed informed consent, patients received ICT01 every 3 weeks with blood samples collected at multiple timepoints for immunophenotyping by flow cytometry and cytokine analysis (IFNγ, TNFα, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-13). Tumor biopsies are collected at baseline and on Day 28 for immunohistochemistry (e.g., BTN3A, γ9δ2 T cells) and expression profiling of cancer- and immunity-related genes. Results: Solid tumor (ST) dose cohorts 1-4 (total n=20) were enrolled and treated with ICT01 doses ranging from 20 μg to 20 mg, and dose cohort 1 of hematologic cancer patients (n=3, 200 μg) has been enrolled. ICT01 was well-tolerated, with no dose-limiting toxicities or related SAEs reported. Target occupancy on T cells at 30 min or 4 hours post first dose ranged from 34% (700 μg, n=2), 79% (2 mg, n=5), 93% (7 mg, n=4) and 100% (20 mg, n=1), with activated γ9δ2 T cells (CD69+) migrating from the blood within 30 min of dosing that led to a &gt; 95% decrease from baseline in the number of circulating γ9δ2 T cells for all 4 doses by 24hrs. The 2nd dose of ICT01 induced a similar activation & migration of γ9δ2 T cells from the circulation. There were no effects on CD4/CD8 T cells, NK, or B cells. Available cytokine data from ST cohorts 1 & 2 showed no CRS although transient 2-3x increases in IFNγ, TNFα, & IL-2 were observed 4 hours post dose in patients with higher baseline γ9δ2 T cell counts. A 5-10x increase of IFNγ was observed on Days 7 & 28 in ST cohort 2, consistent with γ9δ2 T cell activation. Digital pathology analysis of tumor biopsies of a cohort 1 melanoma pt demonstrated a 25x and 8x increase of CD3-TCRgamma delta++ and CD3+ cell densities, respectively, as compared to baseline. Analyses of additional cohorts are ongoing and will be presented. Conclusion: The preliminary results demonstrate that ICT01 safely and potently activates the anti-tumor immune response of γ9δ2 T cells mediated by BTN3A. Citation Format: Aurelien Marabelle, Christiane Jungels, Johann De Bono, Norbert Vey, Martin Wermke, Elena Garralda, Steven Le Gouill, Patricia LoRusso, Aude De Gassart, Emmanuel Valentin, Patrick Brune, Marina Iche, Daniel Olive, Paul A. Frohna. Activation of the antitumor immune response of gamma9delta2 T cells in patients with solid or hematologic malignancies with ICT01, a first-in-class, monoclonal antibody targeting butyrophilin 3A: The EVICTION study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT034

Ozanimod Induction and Maintenance Treatment for Ulcerative Colitis

Ozanimod (RPC1063) is an oral agonist of the sphingosine-1-phosphate receptor subtypes 1 and 5 that induces peripheral lymphocyte sequestration, potentially decreasing the number of activated lymphocytes circulating to the gastrointestinal tract. We conducted a double-blind, placebo-controlled phase 2 trial of ozanimod in 197 adults with moderate-to-severe ulcerative colitis. Patients were randomly assigned, in a 1:1:1 ratio, to receive ozanimod at a dose of 0.5 mg or 1 mg or placebo daily for up to 32 weeks. The Mayo Clinic score was used to measure disease activity on a scale from 0 to 12, with higher scores indicating more severe disease; subscores range from 0 to 3, with higher scores indicating more severe disease. The primary outcome was clinical remission (Mayo Clinic score ≤2, with no subscore >1) at 8 weeks. The primary outcome occurred in 16% of the patients who received 1 mg of ozanimod and in 14% of those who received 0.5 mg of ozanimod, as compared with 6% of those who received placebo (P=0.048 and P=0.14, respectively, for the comparison of the two doses of ozanimod with placebo). Differences in the primary outcome between the group that received 0.5 mg of ozanimod and the placebo group were not significant; therefore, the hierarchical testing plan deemed the analyses of secondary outcomes exploratory. Clinical response (decrease in Mayo Clinic score of ≥3 points and ≥30% and decrease in rectal-bleeding subscore of ≥1 point or a subscore ≤1) at 8 weeks occurred in 57% of those receiving 1 mg of ozanimod and 54% of those receiving 0.5 mg, as compared with 37% of those receiving placebo. At week 32, the rate of clinical remission was 21% in the group that received 1 mg of ozanimod, 26% in the group that received 0.5 mg of ozanimod, and 6% in the group that received placebo; the rate of clinical response was 51%, 35%, and 20%, respectively. At week 8, absolute lymphocyte counts declined 49% from baseline in the group that received 1 mg of ozanimod and 32% from baseline in the group that received 0.5 mg. The most common adverse events overall were anemia and headache. In this preliminary trial, ozanimod at a daily dose of 1 mg resulted in a slightly higher rate of clinical remission of ulcerative colitis than placebo. The trial was not large enough or of sufficiently long duration to establish clinical efficacy or assess safety. (Funded by Receptos; TOUCHSTONE ClinicalTrials.gov number, NCT01647516.

The FINISH-3 trial: A phase 3, international, randomized, single-blind, controlled trial of topical fibrocaps in intraoperative surgical hemostasis

Background This Phase 3, international, randomized, single-blind, controlled trial (FINISH-3) compared the efficacy and safety of Fibrocaps, a ready-to-use, dry-powder fibrin sealant containing human plasma-derived thrombin and fibrinogen, vs gelatin sponge alone for use as a hemostat for surgical bleeding in 4 indications (ie, spinal, hepatic, vascular, soft tissue dissection). Study Design Adults with mild to moderate surgical bleeding (randomized 2:1; Fibrocaps vs gelatin sponge) were treated at a single bleeding site (day 1). Time to hemostasis (TTH) during 5 minutes was compared (log-rank statistic) within each indication. Safety follow-up continued to day 29. Results Patients were treated (Fibrocaps, n = 480; gelatin sponge, n = 239) when undergoing spinal (n = 183), vascular (n = 175), hepatic (n = 180), or soft-tissue (n = 181) procedures. Fibrocaps was applied by spray device in 53% of all procedures (94% of hepatic and soft-tissue procedures). Fibrocaps significantly reduced TTH compared with gelatin sponge; estimated hazard ratios were 3.3, 2.1, 2.3, and 3.4 for the 4 surgical indications, respectively (each p < 0.001; primary end point). Fibrocaps significantly reduced median TTH for each indication (p < 0.001) and was superior for secondary efficacy end points of restricted mean TTH (p < 0.001) and probability of hemostasis at 3 (p < 0.001) and 5 (p ≤ 0.002) minutes. Adverse event incidences were generally similar between treatment arms. Non-neutralizing, anti-thrombin antibodies developed in 2% of Fibrocaps-treated and 3% of gelatin sponge-treated patients. Conclusions Fibrocaps was well tolerated and significantly reduced TTH relative to gelatin sponge alone in all 4 surgical indications. These findings demonstrate the broad utility of Fibrocaps as a hemostatic agent for mild to moderate surgical bleeding