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The immune system employs several checkpoint pathways to regulate responses, maintain homeostasis and prevent self-reactivity and autoimmunity. Tumor cells can hijack these protective mechanisms to enable immune escape, cancer survival and proliferation. Blocking antibodies, designed to interfere with checkpoint molecules CTLA-4 and PD-1/PD-L1 and counteract these immune suppressive mechanisms, have shown significant success in promoting immune responses against cancer and can result in tumor regression in many patients. While inhibitors to CTLA-4 and the PD-1/PD-L1 axis are well-established for the clinical management of melanoma, many patients do not respond or develop resistance to these interventions. Concerted efforts have focused on combinations of approved therapies aiming to further augment positive outcomes and survival. While CTLA-4 and PD-1 are the most-extensively researched targets, results from pre-clinical studies and clinical trials indicate that novel agents, specific for checkpoints such as A2AR, LAG-3, IDO and others, may further contribute to the improvement of patient outcomes, most likely in combinations with anti-CTLA-4 or anti-PD-1 blockade. This review discusses the rationale for, and results to date of, the development of inhibitory immune checkpoint blockade combination therapies in melanoma. The clinical potential of new pipeline therapeutics, and possible future therapy design and directions that hold promise to significantly improve clinical prognosis compared with monotherapy, are discussed.

Ovarian cancer is the most lethal gynaecological cancer and treatment options remain limited. In a recent first-in-class Phase I trial, the monoclonal IgE antibody MOv18, specific for the tumour-associated antigen Folate Receptor-α, was well-tolerated and preliminary anti-tumoural activity observed. Pre-clinical studies identified macrophages as mediators of tumour restriction and pro-inflammatory activation by IgE. However, the mechanisms of IgE-mediated modulation of macrophages and downstream tumour immunity in human cancer remain unclear. Here we study macrophages from patients with epithelial ovarian cancers naive to IgE therapy. High-dimensional flow cytometry and RNA-seq demonstrate immunosuppressive, FcεR-expressing macrophage phenotypes. Ex vivo co-cultures and RNA-seq interaction analyses reveal immunosuppressive associations between patient-derived macrophages and regulatory T (Treg) cells. MOv18 IgE-engaged patient-derived macrophages undergo pro-inflammatory repolarisation ex vivo and display induction of a hyperinflammatory, T cell-stimulatory subset. IgE reverses macrophage-promoted Treg cell induction to increase CD8+ T cell expansion, a signature associated with improved patient prognosis. On-treatment tumours from the MOv18 IgE Phase I trial show evidence of this IgE-driven immune signature, with increased CD68+ and CD3+ cell infiltration. We demonstrate that IgE induces hyperinflammatory repolarised states of patient-derived macrophages to inhibit Treg cell immunosuppression. These processes may collectively promote immune activation in ovarian cancer patients receiving IgE therapy. An IgE antibody recognising Folate Receptor-alpha has been tested in clinical trials for ovarian cancer and preclinical studies show macrophage involvement in the anti-tumoural functions of IgE. Here the authors demonstrate that IgE induces proinflammatory activation of ovarian cancer patient macrophages, which reverses their immunosuppressive induction of Treg cells and promotes CD8 + T cell function.

BackgroundCancer immunotherapy with monoclonal antibodies and chimeric antigen receptor (CAR) T cell therapies can benefit from selection of new targets with high levels of tumor specificity and from early assessments of efficacy and safety to derisk potential therapies.MethodsEmploying mass spectrometry, bioinformatics, immuno-mass spectrometry and CRISPR/Cas9 we identified the target of the tumor-specific SF-25 antibody. We engineered IgE and CAR T cell immunotherapies derived from the SF-25 clone and evaluated potential for cancer therapy.ResultsWe identified the target of the SF-25 clone as the tumor-associated antigen SLC3A2, a cell surface protein with key roles in cancer metabolism. We generated IgE monoclonal antibody, and CAR T cell immunotherapies each recognizing SLC3A2. In concordance with preclinical and, more recently, clinical findings with the first-in-class IgE antibody MOv18 (recognizing the tumor-associated antigen Folate Receptor alpha), SF-25 IgE potentiated Fc-mediated effector functions against cancer cells in vitro and restricted human tumor xenograft growth in mice engrafted with human effector cells. The antibody did not trigger basophil activation in cancer patient blood ex vivo, suggesting failure to induce type I hypersensitivity, and supporting safe therapeutic administration. SLC3A2-specific CAR T cells demonstrated cytotoxicity against tumor cells, stimulated interferon-γ and interleukin-2 production in vitro. In vivo SLC3A2-specific CAR T cells significantly increased overall survival and reduced growth of subcutaneous PC3-LN3-luciferase xenografts. No weight loss, manifestations of cytokine release syndrome or graft-versus-host disease, were detected.ConclusionsThese findings identify efficacious and potentially safe tumor-targeting of SLC3A2 with novel immune-activating antibody and genetically modified cell therapies.

Basophils are involved in manifestations of hypersensitivity, however, the current understanding of their propensity for activation and their prognostic value in cancer patients remains unclear. As in healthy and atopic individuals, basophil populations were identified in blood from ovarian cancer patients (n = 53) with diverse tumor histologies and treatment histories. Ex vivo basophil activation was measured by CD63 expression using the basophil activation test (BAT). Irrespective of prior treatment, basophils could be activated by stimulation with IgE- (anti-FcεRI and anti-IgE) and non-IgE (fMLP) mediated triggers. Basophil activation was detected by ex vivo exposure to paclitaxel, but not to other anti-cancer therapies, in agreement with a clinical history of systemic hypersensitivity reactions to paclitaxel. Protein and gene expression analyses support the presence of basophils (CCR3, CD123, FcεRI) and activated basophils (CD63, CD203c, tryptase) in ovarian tumors. Greater numbers of circulating basophils, cells with greater capacity for ex vivo stimulation (n = 35), and gene signatures indicating the presence of activated basophils in tumors (n = 439) were each associated with improved survival in ovarian cancer. Circulating basophils in cancer patients respond to IgE- and non-IgE-mediated signals and could help identify hypersensitivity to therapeutic agents. Activated circulating and tumor-infiltrating basophils may be potential biomarkers in oncology.

All antibodies approved for cancer therapy are monoclonal IgGs but the biology of IgE, supported by comparative preclinical data, offers the potential for enhanced effector cell potency. Here we report a Phase I dose escalation trial (NCT02546921) with the primary objective of exploring the safety and tolerability of MOv18 IgE, a chimeric first-in-class IgE antibody, in patients with tumours expressing the relevant antigen, folate receptor-alpha. The trial incorporated skin prick and basophil activation tests (BAT) to select patients at lowest risk of allergic toxicity. Secondary objectives were exploration of anti-tumour activity, recommended Phase II dose, and pharmacokinetics. Dose escalation ranged from 70 μg–12 mg. The most common toxicity of MOv18 IgE is transient urticaria. A single patient experienced anaphylaxis, likely explained by detection of circulating basophils at baseline that could be activated by MOv18 IgE. The BAT assay was used to avoid enrolling further patients with reactive basophils. The safety profile is tolerable and maximum tolerated dose has not been reached, with evidence of anti-tumour activity observed in a patient with ovarian cancer. These results demonstrate the potential of IgE therapy for cancer. IgE antibodies have shown anti-tumor activity, even superior to IgG, in preclinical models. However, all monoclonal antibodies in clinical use for cancer therapy are members of the IgG class. Here the authors report the results of a phase I clinical trial of a chimeric monoclonal IgE antibody, specific for the folate receptor-alpha, in patients with advanced solid cancer.

The aim of this study is to fabricate a Cu-0.5wt%TiB2 composite by mechanical alloying (MA) and spark plasma sintering (SPS). Increasing the milling time, the powders are subjected firstly to a severe flattening process and then to intense welding, which promotes the refinement of TiB2 particles, their uniform dispersion in the metal matrix, and the adhesion between the two constituents. Sintered metal matrix composites (MMC) exhibit density values between 99 and 96%, which are generally decreased by increasing milling time in view of the stronger strain hardening. On the other side, the hardness increases with milling time due to the refinement of TiB2 particles and their improved distribution. The hardness of MMC is three times higher (225 HV0.05) than the starting hardness of atomized copper (90 HV0.05). Tensile tests show a loss of ductility, but ultimate tensile strength has been increased from 276 MPa of atomized copper to 489 MPa of MMC milled for 240 min. The thermal conductivity of MMC is comparable to that of atomized copper (300 W/mK), i.e., much higher than that of the commercial Cu-Be alloy (Uddeholm Moldmax HH, 106 W/mK) typically used for tooling applications.

Background/Objectives: Children with above-average cognitive functioning often present complex developmental profiles, combining high cognitive potential with heterogeneous socio-emotional and learning trajectories. Although the cognitive and behavioral characteristics of giftedness have been widely studied in Anglophone countries, evidence remains limited in Southern Europe. This study aimed to investigate the cognitive, academic, and emotional–behavioral profiles of Italian children and adolescents with above-average cognitive functioning, using an inclusive, dimensional approach (IQ > 114). Methods: We analyzed a cross-sectional sample of 331 children and adolescents (ages 2.11–16.5 years), referred for clinical cognitive or behavioral evaluations. Participants were assessed using the WPPSI-III or WISC-IV for cognitive functioning, the MT battery for academic achievement, and the Child Behavior Checklist (CBCL) for emotional and behavioral symptoms. Comparative and correlational analyses were performed across age, gender, and functional domains. A correction for multiple testing was applied using the Benjamini–Hochberg procedure. Results: Gifted participants showed strong verbal comprehension (mean VCI: preschoolers = 118; school-aged = 121) and relative weaknesses in working memory (WM = 106) and processing speed (PS = 109). Males outperformed females in perceptual reasoning (PR = 121 vs. 118; p = 0.032), while females scored higher in processing speed (112 vs. 106; p = 0.021). Difficulties in writing and arithmetic were observed in 47.3% and 41.8% of school-aged participants, respectively. Subclinical internalizing problems were common in preschool and school-aged groups (mean CBCL T = 56.2–56.7). Working memory negatively correlated with total behavioral problems (r = −0.13, p = 0.046). Conclusions: These findings confirm the heterogeneity of gifted profiles and underscore the need for personalized educational and psychological interventions to support both strengths and vulnerabilities in gifted children. Caution is warranted when interpreting these associations, given their modest effect sizes and the exploratory nature of the study.

PurposeIt is still not clear the role of perilesional biopsy (PL) and the extension of the random biopsy (RB) scheme to be adopted during mpMRI-guided ultrasound fusion biopsy (FB). To evaluate the increase in diagnostic accuracy achieved by PL and different RB schemes over target biopsy (TB).MethodsWe collected prospectively 168 biopsy-naïve patients with positive mpMRI receiving FB and concurrent 24-core RB. The diagnostic yields of the different possible biopsy schemes (TB only; TB + 4 PL cores; TB + 12-core RB; TB + 24-core RB) were compared by the McNemar test. Clinically significant (CS) prostate cancer (PCA) was defined according to the definition of the PROMIS trial. Regression analyses were used to identify independent predictors of the presence of any cancer, csPCA.ResultsThe detection rate of CS cancers increased to 35%, 45%, and 49% by adding 4 PL cores, 12, and 24 RB cores, respectively (all p < 0.02). Notably, the largest scheme including 3 TB and 24 RB cores identified a small but statistically significant 4% increase in detection rate of CS cancer, as compared with the second largest scheme. TB alone identified only 62% of the CS cancers. Such figure increased to 72% by adding 4 PL cores, and to 91% by adding 14 RB cores.ConclusionsWe found that PL biopsy increased the detection rate of CS cancers as compared with TB alone. However, the combination of those cores missed about 30% of the CS cancers identified with larger RB cores, notably including a considerable 15% of cases located contralaterally to the index tumor.

Background Based on the findings of different trials in biopsy naïve patients, target biopsy (TB) plus random biopsy (RB) during mpMRI-guided transrectal ultrasound fusion biopsy (FB) are often also adopted for the biopsy performed during active surveillance (AS) programs. At the moment, a clear consensus on the extent and modalities of the procedure is lacking. Objective To evaluate the increase in diagnostic accuracy achieved by perilesional biopsy (PL) and different RB schemes during FB performed in AS protocol. Design, setting, and participants We collected prospectively the data of 112 consecutive patients with low- or very-low-risk prostate cancer; positive mpMRI underwent biopsy at a single academic institution in the context of an AS protocol. Intervention(s) mpMRI/transrectal US FB with Hitachi RVS system with 3 TB and concurrent transrectal 24-core RB. Outcome measurements and statistical analysis The diagnostic yield of the different possible biopsy schemes (TB only; TB + 4 perilesional (PL) cores; TB + 12-core RB; TB + 24-core RB) was compared by the McNemar test. Univariable and multivariable regression analyses were adopted to identify predictors of any cancer, Gleason grade group (GGG) ≥2 cancers, and the presence of GGG≥2 cancers in the larger schemes only. Results and limitations The detection rate of GGG ≥2 cancers increased to 30%, 39%, and 49% by adding 4 PL cores, 14, and 24 RB cores, respectively, to TB cores (all p values <0.01). On the whole, TB alone, 14-core RB, and 24-core-RB identified 38%, 47%, and 56% of all the GGG ≥2 cancers. Such figures increased to 62% by adding to TB 4 PL cores, and to 80% by adding 14 RB cores. Most of the differences were observed in PI-RADS 4 lesions. Conclusions We found that PL biopsy increased the detection rate of GGG ≥2 cancers as compared with TB alone. However, the combination of those cores missed a large percentage of the CS cancers identified with larger RB cores, including a 20% of CS cancers diagnosed only by the combination of TB plus 24-core RB.

This retrospective observational study was based on databases of the Local Health Authority of Treviso, Italy. It evaluated the prevalence and the effectiveness of oral anticoagulation treatment (OAT) for the management of nonvalvular atrial fibrillation (NVAF) in everyday clinical practice. Out of 6,138 NVAF patients, only 3,024 received vitamin K antagonist (VKA). Potential barriers decreasing the probability of being treated with VKA were female sex, older age, antiplatelet treatment and history of bleeding. In addition, VKA-treatment was not in line with current ESC and AIAC guidelines, since the patients at high or low risk of stroke were under- or over-treated, resp. Among VKAtreated patients, 73 % of subjects were not at target with anticoagulation. OAT resulted to be effective in reducing stroke risk. However, stroke events were significantly influenced also by previous stroke or transient ischemic attack (hazard ratio, HR = 2.99, p < 0.001) and by previous bleeding events (HR = 1.60, p < 0.001).