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Background C ytokine i nduced m emory- l ike natural killer (CIML NK) cells combined with an IL-15 super-agonist (N-803) are a novel modality to treat relapsed/refractory head and neck cancer. Methods We report data from a phase I trial of haploidentical CIML NK cells combined with N-803 with or without ipilimumab (IPI) in relapsed/refractory head and neck cancer patients after a median of 6 prior lines of therapy. The trial adhered to a 3 + 3 dose de-escalation design, with primary endpoint being safety. High-resolution immunophenotypic and transcriptional profiling characterized the NK cells and their interacting partners in vivo. Results The primary safety endpoint was established, with dose-limiting toxicity in 1/10 patients. A transient disease control rate correlated with donor NK cell expansion, the latter occurring irrespective of IPI. The combination of CIML NK cells with N-803 and IPI was associated with increased early NK cell proliferation, contraction of Treg: Tcon, rapid recovery of recipient CD8 + T cells, and subsequent accelerated rejection of donor NK cells. Conclusions CIML NK cells combined with N-803 and ipilimumab to treat head and neck cancer is safe, and associated with a more proliferative NK cell phenotype. However, the combination leads to reduced HLA mismatched NK cell persistence, resulting in an important limitation affecting NK cell combination therapies in clinical trials. These results inform evaluation of CIML NK therapy for advanced malignancies, with considerations for combination with IPI. Trial Registration NCT04290546.

The tumor microenvironment can inhibit the efficacy of cancer therapies through mechanisms such as poor trafficking and exhaustion of immune cells. Here, to address this challenge, we exploited the safety, tumor tropism and ease of genetic manipulation of non-pathogenic Escherichia coli ( E. coli ) to deliver key immune-activating cytokines to tumors via surface display on the outer membrane of E. coli K-12 DH5α. Non-pathogenic E. coli expressing murine decoy-resistant IL18 mutein (DR18) induced robust CD8 + T and natural killer (NK) cell-dependent immune responses and suppressed tumor progression in immune-competent colorectal carcinoma and melanoma mouse models. E. coli K-12 DH5α engineered to display human DR18 potently activated mesothelin-targeting chimeric antigen receptor (CAR) NK cells and enhance their trafficking into tumors, which extended survival in an NK cell treatment-resistant mesothelioma xenograft model by enhancing TNF signaling and upregulating NK activation markers. Our live bacteria-based immunotherapeutic system safely and effectively induces potent anti-tumor responses in treatment-resistant solid tumors, motivating further evaluation of this approach in the clinic. Bacteria expressing an anti-tumor cytokine act as a potent cancer immunotherapy.

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels ( p  = 0.0006, CI 95%: 4.12, 13.32) and particle number ( p  = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration ( p  = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity ( p  = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele. Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.

ObjectivesPremature cardiovascular events in systemic lupus erythematosus (SLE) contribute to morbidity and mortality, with no effective preventive strategies described to date. Immune dysregulation and metabolic disturbances appear to play prominent roles in the induction of vascular disease in SLE. The peroxisome proliferator activated receptor-gamma agonist pioglitazone (PGZ suppresses vascular damage and immune dysregulation in murine lupus and improves endothelial dysfunction in other inflammatory diseases. We hypothesised that PGZ could improve vascular dysfunction and cardiometabolic parameters in SLE.MethodsEighty SLE subjects with mild to severe disease activity were randomised to a sequence of PGZ followed by placebo for 3 months, or vice versa, in a double-blind, cross-over design with a 2-month wash-out period. Primary endpoints were parameters of endothelial function and arterial inflammation, measured by multimodal assessments. Additional outcome measures of disease activity, neutrophil dysregulation, metabolic disturbances and gene expression studies were performed.ResultsSeventy-two subjects completed the study. PGZ was associated with a significant reduction in Cardio-Ankle Vascular Index (a measure of arterial stiffness) compared with placebo. Various metabolic parameters improved with PGZ, including insulin resistance and lipoprotein profiles. Circulating neutrophil extracellular trap levels also significantly decreased with PGZ compared with placebo. Most adverse events experienced while on PGZ were mild and resolved with reduction in PGZ dose.ConclusionPGZ was well tolerated and induced significant improvement in vascular stiffness and cardiometabolic parameters in SLE. The results suggest that PGZ should be further explored as a modulator of cardiovascular disease risk in SLE.Trial registration number NCT02338999.

Background: Cannabidiol (CBD) has been shown recently to positively affect patient pain and satisfaction immediately after arthroscopic rotator cuff repair (ARCR). However, it is unclear whether the addition of CBD to a perioperative regimen could affect postoperative outcomes. Purpose: To evaluate patient-reported outcomes among patients who underwent ARCR and received buccally absorbed CBD or an identical placebo for early postoperative pain management at 1-year follow-up. Study Design: Randomized controlled trial; Level of evidence, 2. Methods: Eligible patients had previously participated in a multicenter, placebo-controlled, randomized, double-blinded trial that evaluated the analgesic effects of CBD in the immediate postoperative period after ARCR. The experimental group received 25 mg of CBD 3 times/day if <80 kg and 50 mg of CBD 3 times/day if >80 kg for 14 days, with the control group receiving an identical placebo. The following outcomes were assessed at minimum 1-year follow-up: visual analog scale (VAS) for pain, American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numeric Evaluation (SANE), and patient satisfaction. The rates of achievement of the Patient Acceptable Symptom State (PASS) were compared based on ASES at latest follow-up. Continuous and categorical variables were compared with the Mann-Whitney U test and Fisher exact test, respectively. Results: Follow-up was obtained from 83 of 99 patients (83.8%) who completed the original trial. There were no significant differences between the CBD and control groups with respect to age, sex, body mass index, rate of concomitant procedures, or number of anchors used intraoperatively. At 1-year follow-up, there were no significant differences between the CBD and control groups in VAS pain (0.8 vs 1.2, P = .38), ASES (93.0 vs 91.1, P = .71), SANE (87.6 vs 90.1, P = .24), or satisfaction (97.4 vs 95.4, P = .41). A majority of patients achieved the PASS (81.0% [CBD] vs 77.5% [control]; P = .79). Conclusion: Perioperative use of CBD for pain control among patients undergoing ARCR did not result in any significant deficits in pain, satisfaction, or patient-reported outcomes at 1-year postoperatively compared with a placebo control group. These findings suggest that CBD can be considered in a postoperative multimodal pain management regimen without detrimental effects on outcome. Registration: NCT04672252 (ClinicalTrials.gov identifier).

This paper describes the climate-related forcings (CRFs), i.e. change in climate comprising the atmosphere and the ocean, coastal water levels, and atmospheric composition (CO2 and methane concentrations), provided as input data within the “b” part of the third simulation round of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP3b). While ISIMIP3a comprises historical impact models simulations forced by observational Direct Human Forcings (DHF), such as changes in population and asset distributions, land use, fishing efforts, agricultural and water management driven by socio-economic development or climate protection strategies, and observational CRF, the ISIMIP3b CRFs are based on climate model simulations generated within the sixth phase of the Coupled Model Intercomparison Project (CMIP6). In a first set of experiments covering the pre-industrial (1601–1849) and historical period (1850–2014) (ISIMIP3b, group I) the CMIP6-based CRFs for the historical period are combined with historical observation-based DHF also considered in ISIMIP3a. These group I simulations allow for the quantification of impacts of historical climate change by comparison to simulations where the observational DHF are combined with simulated pre-industrial CRFs. In addition, the impacts of observed changes in CRFs can be compared to the impacts of simulated changes in CRFs by comparing the ISIMIP3a simulations to the ISIMIP3b, group I simulations. The second group of experiments (ISIMIP3b, group II) comprises future projections assuming constant observational direct human forcings at 2015 levels to estimate the impact of climate change given today's DHF for the low emission scenario SSP1-2.6, the high and the very high emission scenarios SSP3-7.0, SSP5-8.5, and reference simulations based on pre-industrial CRF, respectively. The very high emissions scenarios and the assumption of fixed present day DHF particularly allow for testing the scalability of impacts in terms of global temperature change. The provided CRFs comprise atmospheric CO2 and CH4 concentrations, atmospheric and oceanic climate data, coastal water levels, tropical cyclone (TC) tracks and their associated wind speed and precipitation fields. In addition to the CRFs data, this paper describes the experiments belonging to group I and II and the rationale behind them. Another set of future projections accounting for changing DHFs (ISIMIP3b, group III) is in preparation and will be described in another paper.

Durante siglos, los territorios bañados por el mar Adriático han sido punto de encuentro de un efervescente intercambio comercial y cultural. Allí se entrecruzan constantemente los caminos de Occidente y Oriente, conviven católicos, ortodoxos y musulmanes, y comparten mirada los universos latino y balcánico. Ahora, cuando el mapa geopolítico de Europa se ha desplazado hacia el sur, hacia un Mediterráneo fronterizo con África y el Oriente Próximo, la región adriática está a punto de alcanzar una nueva relevancia, no ya continental, sino global. Es una zona donde se viven en primer plano los nuevos populismos, las batallas energéticas, las crisis de los refugiados y el renovado poder de Rusia y China. En este revelador libro, Robert D. Kaplan ofrece una sorprendente combinación de literatura de viajes, ensayo histórico y, sobre todo, certero análisis geopolítico, para conocer el pasado europeo reciente y el futuro mundial a medio plazo.