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The capacity to use CAR T-cell therapy has been limited by the need to produce cells in a specialized laboratory. In this study, 40% of patients with relapsed or refractory diffuse large B-cell lymphoma may have had durable complete responses with cells manufactured in a central commercial laboratory.

In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing. Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Novartis Pharmaceuticals.

Background The availability of alcohol is a major factor in underage drinking and according to the alcohol harm paradox, those living in more deprived communities are more susceptible to the negative consequences of alcohol use, despite drinking the same or less than those from more affluent areas. Alcohol availability within the vicinity of the home or school normalises alcohol for schoolchildren. For the first time in the Republic of Ireland, this study examines the number of premises licensed to sell alcohol within 300 m of all schools in Ireland and differences in this number between disadvantaged and non-disadvantaged schools. Methods Using publicly available data from the Department of Education and Revenue, the addresses of all schools ( n  = 3,958) and all premises with at least one liquor licence ( n  = 14,840) were geocoded and analysed using the Geographic Information System software, Quantum GIS (QGIS). Schools were identified by their disadvantaged classification using the HP Pobal Deprivation Index and the number of liquor licences within 300 m of each school type was examined. To test for significant differences between schools’ level of disadvantage, a combination of Mann-Whitney U tests, Kruskal-Wallis tests and Dunn-Bonferroni tests were used. Results There was a mean of two licenced premises within 300 m of all schools in Ireland, but when disadvantaged schools were compared to non-disadvantaged schools, there was a significantly higher number of licenced premises around disadvantaged schools ( p  < .001). Primary schools are further classified according to their level of disadvantage and the results indicated that those schools classified as the most disadvantaged had a significantly greater number of liquor licences within 300 meters ( p  < .001). There was no significant difference in density of licenced premises when comparing disadvantaged secondary schools with non-disadvantaged secondary schools ( p  = .705). Conclusion Ireland is considering increasing alcohol availability through the Sale of Alcohol Bill, 2022. However, this analysis indicates already problematic numbers of licenced premises within close proximity of schools in Ireland. It is essential that the harms associated with alcohol availability are considered, especially for those living and attending school in disadvantaged communities, where higher numbers of licenced premises were identified.

Pretreatment with anti-thymocyte globulin (ATG) decreases the occurrence of chronic graft-versus-host disease (CGVHD) after haemopoietic cell transplantation from an unrelated donor, but evidence of patient benefit is absent. We did a study to test whether ATG provides patient benefit, particularly in reducing the need for long-term immunosuppressive treatment after transplantation. We did a phase 3, multicentre, open-label, randomised controlled trial at ten transplant centres in Canada and one in Australia. Eligible patients were aged 16 to 70 years with any haematological malignancy and a Karnofsky score of at least 60 receiving either myeloablative or non-myeloablative (or reduced intensity) conditioning preparative regimens before haemopoietic cell transplantation from an unrelated donor. We allocated patients first by simple randomisation (1:1), then by a minimisation method, to either pretransplantation rabbit ATG plus standard GVHD prophylaxis (ATG group) or standard GVHD prophylaxis alone (no ATG group). We gave a total dose of ATG of 4·5 mg/kg intravenously over 3 days (0·5 mg/kg 2 days before transplantation, 2·0 mg/kg 1 day before, and 2·0 mg/kg 1 day after). The primary endpoint was freedom from all systemic immunosuppressive drugs without resumption up to 12 months after transplantation. Analysis was based on a modified intention-to-treat method. This trial was registered at ISRCTN, number 29899028. Between June 9, 2010, and July 8, 2013, we recruited and assigned 203 eligible patients to treatment (101 to ATG and 102 to no ATG). 37 (37%) of 99 patients who received ATG were free from immunosuppressive treatment at 12 months compared with 16 (16%) of 97 who received no ATG (adjusted odds ratio 4·25 [95% CI 1·87–9·67]; p=0·00060. The occurrence of serious adverse events (Common Terminology Criteria grades 4 or 5) did not differ between the treatment groups (34 [34%] of 99 patients in the ATG group vs 41 [42%] of 97 in the no ATG group). Epstein-Barr virus reactivation was substantially more common in patients who received ATG (20 [one of whom died—the only death due to an adverse event]) versus those who did not receive ATG (two [no deaths]). No deaths were attributable to ATG. ATG should be added to myeloblative and non-myeloblative preparative regimens for haemopoietic cell transplantation when using unrelated donors. The benefits of decreases in steroid use are clinically significant. Epstein-Barr virus reactivation is increased, but is manageable by prospective monitoring and the use of rituximab. Future trials could determine whether the doses of ATG used in this trial are optimum, and could also provide additional evidence of a low relapse rate after non-myeloablative regimens. The Canadian Institutes of Health Research and Sanofi.

Enzyme and chaperone therapies are used to treat Fabry disease. Such treatments are expensive and require intrusive biweekly infusions; they are also not particularly efficacious. In this pilot, single-arm study (NCT02800070), five adult males with Type 1 (classical) phenotype Fabry disease were infused with autologous lentivirus-transduced, CD34 + -selected, hematopoietic stem/progenitor cells engineered to express alpha-galactosidase A (α-gal A). Safety and toxicity are the primary endpoints. The non-myeloablative preparative regimen consisted of intravenous melphalan. No serious adverse events (AEs) are attributable to the investigational product. All patients produced α-gal A to near normal levels within one week. Vector is detected in peripheral blood and bone marrow cells, plasma and leukocytes demonstrate α-gal A activity within or above the reference range, and reductions in plasma and urine globotriaosylceramide (Gb 3 ) and globotriaosylsphingosine (lyso-Gb 3 ) are seen. While the study and evaluations are still ongoing, the first patient is nearly three years post-infusion. Three patients have elected to discontinue enzyme therapy. Treatments for Fabry disease, an inherited lysosomal disorder caused by the deficiency of the enzyme alpha-galactosidase A, are not fully efficacious. Here the authors report a single-arm phase I trial of gene therapy with autologous, lentivirus-transduced, hematopoietic cells that express alpha-galactosidase A to demonstrate that this approach is safe in five patients with Fabry disease.

Background Bone marrow cytology is required to make a hematological diagnosis, influencing critical clinical decision points in hematology. However, bone marrow cytology is tedious, limited to experienced reference centers and associated with inter-observer variability. This may lead to a delayed or incorrect diagnosis, leaving an unmet need for innovative supporting technologies. Methods We develop an end-to-end deep learning-based system for automated bone marrow cytology. Starting with a bone marrow aspirate digital whole slide image, our system rapidly and automatically detects suitable regions for cytology, and subsequently identifies and classifies all bone marrow cells in each region. This collective cytomorphological information is captured in a representation called Histogram of Cell Types (HCT) quantifying bone marrow cell class probability distribution and acting as a cytological patient fingerprint. Results Our system achieves high accuracy in region detection (0.97 accuracy and 0.99 ROC AUC), and cell detection and cell classification (0.75 mean average precision, 0.78 average F1-score, Log-average miss rate of 0.31). Conclusions HCT has potential to eventually support more efficient and accurate diagnosis in hematology, supporting AI-enabled computational pathology. Plain language summary Identifying and counting cells in bone marrow samples, known as cytology, is critical for the diagnosis of blood disorders. This is a complex and labor-intensive process, with some variation in how hematopathologists interpret these samples. Here, we develop an artificial intelligence system for automated bone marrow cytology, which automatically detects and identifies all types of cells found in the bone marrow. This information is summarized in a chart that we call the Histogram of Cell Types (HCT), a new way to represent complex information generated in bone marrow cytology. Our system achieves high accuracy and precision in classifying the different types of bone marrow cells as a HCT. This tool may eventually help clinicians to make more efficient and accurate diagnoses. Moosavi Tayebi et al. develop a deep learning-based computational pathology tool for automated bone marrow cytology from whole slide images. Their approach generates a histogram of cell types present within the bone marrow aspirate to aid in diagnostic haematopathology.

T cells are the current choice for many cell therapy applications. They are relatively easy to access, expand in culture, and genetically modify. Rapamycin‐conditioning ex vivo reprograms T cells, increasing their memory properties and capacity for survival, while reducing inflammatory potential and the amount of preparative conditioning required for engraftment. Rapamycin‐conditioned T cells have been tested in patients and deemed to be safe to administer in numerous settings, with reduced occurrence of infusion‐related adverse events. We demonstrate that ex vivo lentivirus‐modified, rapamycin‐conditioned CD4 + T cells can also act as next‐generation cellular delivery vehicles—that is, “micropharmacies”—to disseminate corrective enzymes for multiple lysosomal storage disorders. We evaluated the therapeutic potential of this treatment platform for Fabry, Gaucher, Farber, and Pompe diseases in vitro and in vivo . For example, such micropharmacies expressing α‐galactosidase A for treatment of Fabry disease were transplanted in mice where they provided functional enzyme in key affected tissues such as kidney and heart, facilitating clearance of pathogenic substrate after a single administration. Synopsis The therapeutic potential of lentivirus (LV)‐modified, rapamycin‐conditioned CD4 + T cells (T‐Rapa) was evaluated. These T‐Rapa “micropharmacies” (TRaMs) can be used as next‐generation cellular delivery vehicles to treat Lysosomal Storage Disorders (LSDs) and other inherited disorders. LV vectors were developed to engineer overexpression and secretion of α‐galactosidase A (α‐gal A), glucocerebrosidase (GCase), acid ceramidase (ACDase), and acid α‐glucosidase (GAA). TRaMs generated from healthy donors (HDo) generated considerable levels of functional secreted enzyme when vector‐modified; and maintained secretion even when quiescent. TRaMs manufactured from Fabry patient donor cells (FDo) had high intracellular and secreted α‐gal A activities. α‐Gal A produced by TRaMs showed appropriate glycosylation and could be taken up by Fabry patient‐derived fibroblasts in vitro . Xenografted TRaMs reduced or, in some cases, normalized Gb3 and lyso‐Gb3 substrate levels in plasma and key tissues in a Fabry mouse model. Graphical Abstract The therapeutic potential of lentivirus (LV)‐modified, rapamycin‐conditioned CD4 + T cells (T‐Rapa) was evaluated. These T‐Rapa \"micropharmacies\" (TRaMs) can be used as next‐generation cellular delivery vehicles to treat Lysosomal Storage Disorders (LSDs) and other inherited disorders.

Advances in visualisation techniques provide new ways for us to explore how we introduce complex topics like remote sensing to non-specialist audiences. Taking inspiration from the popularity of augmented reality (AR) apps, a free, mobile digital AR app titled SatelliteSkill5, has been developed for both Androids and iPhones in Unity AR. SatelliteSkill5 helps users conceptualise remote sensing (RS) theory and technology by showcasing the potential of datasets such as multispectral images, SAR backscatter, drone orthophotography, and bathymetric LIDAR for tackling real-world challenges, with examples tackling many of the United Nations’ Sustainable Development Goals (SDGs) as the focus. Leveraging tried and tested pedagogic practices such as active learning, game-based learning, and targeting cross-curricular topics, SatelliteSkill5 introduces users to many of the fundamental geospatial data themes identified by the UN as essential for meeting the SDGs, imparting users with a familiarity of concepts such as land cover, elevation, land parcels, bathymetry, and soil. The SatelliteSkill5 app was piloted in 12 Irish schools during 2021 and 2022 and with 861 students ranging from 12 to 18 years old. This research shows that both students and teachers value learning in an easy-to-use AR environment and that SDGs help users to better understand complex remote sensing theory.

Introduction Chimeric antigen receptor T‐cell (CART) therapy has shown clinical efficacy in relapsed and refractory large B‐cell malignancies. There is emerging data on the long‐term complications including risk of secondary malignancies. We aimed to describe the incidence and characteristics of secondary malignancies following CART therapy. Methods We performed a single‐center retrospective analysis of a prospectively collected cohort of 87 patients who received CART therapy for relapsed/refractory B‐cell malignancies between January 2020 and August 2023. Results Seven patients (8.0%) developed a secondary malignancy, with a median age of 57 years (40–77) and mean time to onset of 16.9 months (3–34.5 months). Two patients were diagnosed with MDS and five with AML. Six patients had cytogenetic abnormalities at diagnosis of MDS/AML. Five patients received hypomethylating agents and two received an allogeneic stem cell transplant as treatment for their myeloid malignancy. Two patients were alive at 12 months after diagnosis of their myeloid malignancy. The 12‐month cumulative incidence function (CIF) was 2.3% (95% CI, 0.4%–7.3%) and the 24‐month CIF was 6.9% (95% CI, 2.4%–14.4%). Conclusion Development of a secondary malignancy is a potential complication following CART therapy. Results of this single‐center study should be confirmed with larger multicenter studies. Trial Registration: The authors have confirmed clinical trial registration is not needed for this submission.