CAR-T cell therapy in paediatric acute lymphoblastic leukaemia - past, present and future

Over the last decade, chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment modality for relapsed/refractory B-cell malignancies in both children and adults. As an adoptive immune therapy, CAR-T cells have the potential to overcome disease that is resistant to chemo- and radiotherapy as well as represent a viable option for those who have already reached toxicity ceilings with standard therapies. CD19-directed CAR-T cell products have been licensed for use in paediatric B-cell acute lymphoblastic leukaemia that is refractory, in relapse post-transplant or in second or later relapse. Many challenges remain, rightly resulting in a heavily-mined research field. These include mitigating short-term immune-mediated toxicity, maintaining durability of responses, broadening treatment accessibility and extending its applicability to other malignant settings. In this review, dedicated to marking 60 years since the establishment of the British Society for Haematology, we will focus on the contribution of our community towards the success of CD19-directed CAR-T cell therapy in children. We will put current practice in CAR-T cell therapy into the context of future challenges to be addressed in order for it to fulfil its "game-changing" therapeutic potential

Materials and Textile Architecture Analyses for Mechanical Counter-Pressure Space Suits using Active Materials

Mechanical counter-pressure (MCP) space suits have the potential to improve the mobility of astronauts as they conduct planetary exploration activities. MCP suits differ from traditional gas-pressurized space suits by applying surface pressure to the wearer using tight-fitting materials rather than pressurized gas, and represent a fundamental change in space suit design. However, the underlying technologies required to provide uniform compression in a MCP garment at sufficient pressures for space exploration have not yet been perfected, and donning and doffing a MCP suit remains a significant challenge. This research effort focuses on the novel use of active material technologies to produce a garment with controllable compression capabilities (up to 30 kPa) to address these problems. We provide a comparative study of active materials and textile architectures for MCP applications; concept active material compression textiles to be developed and tested based on these analyses; and preliminary biaxial braid compression garment modeling results.United States. National Aeronautics and Space Administration (OCT Space Technology Research Fellowship Grant NNX11AM62H)MIT-Portugal Progra

Intake pattern and nutrient supply of lactating sheep selecting dried forage from woody plants and straw offered in binary or multiple choice

This study investigated whether offering either binary or multiple choice among low quality forages has an effect on intake and feeding behaviour compared to no-choice situations where only one single low-quality forage is offered. Forages from different woody plants and straw were tested in lactating sheep either in Syria (Exp. 1; Awassi sheep) or in Switzerland (Exp. 2; East Friesian Dairy sheep). Artemisia herba-alba, Atriplex leucoclada, Haloxylon articulatum, Noaea mucronata, and Salsola vermiculata were used in Exp. 1. The three most preferred plants (A. leucoclada, H. articulatum and S. vermiculata) were tested again in Exp. 2 together with Betula pendula, Castanea sativa and Juglans regia. Both experiments started with a binary choice test where one plant and barley straw were offered separately for 4 h in the morning to six sheep (test period) in a random sequence in consecutive 7-day sub-periods. A control group (n = 6 per experiment) received only straw in the test period. For the rest of the day, a basal diet composed of straw ad libitum and concentrate was offered. After the binary choice test, two 2-week periods followed, where in the first straw only and in the second all test plants were offered to all animals from both groups to ascertain equal familiarisation with all plants. For the following 7-day multiple choice test animals were allocated to two new groups. The ‘multiple choice’ group could choose among all test plants and straw during the 4-h test period, the ‘control’ group received only the basal diet. Intakes of test feeds during 4 h and 24 h as well as feeding behaviour during the first 30 min were recorded. Additionally, nutrient intake was determined. Total daily test feed intake was always higher in the choice groups, but this was more pronounced in the multiple choice situation (Exp. 1: 30 and 48, Exp. 2: 49 and 74 g dry matter/kg live-weight0.75 with ‘control’ and ‘multiple choice’, respectively). A. leucoclada (Exp. 1; proportionately 0.73 of total test plant intake) and B. pendula (Exp. 2; 0.87) were the preferred plants in the multiple choice test and also with binary choice. Most other feeds were only consumed in low amounts in the binary and even less in multiple choice situations. In conclusion, giving sheep the choice among low quality forages seemed to be advantageous. Even though in both experiments animals preferred especially one plant, choice still facilitated intake

A Human Neurovascular Unit On-a-Chip

Protection of the central nervous system (CNS) and cerebral homeostasis depend upon the blood–brain barrier (BBB) functions and permeability. BBB restrictive permeability hinders drug delivery for the treatment of several neurodegenerative diseases and brain tumors. Several in vivo animal models and in vitro systems have been developed to understand the BBB complex mechanisms and aid in the design of improved therapeutic strategies. However, there are still many limitations that should be addressed to achieve the structural and chemical environment of a human BBB. We developed a microfluidic-based model of the neurovascular unit. A monolayer of human cerebral endothelial cells (hCMEC-D3) was grown and cocultured with human brain microvascular pericytes (hBMVPC), and human induced pluripotent stem cells differentiated into astrocytes (hiPSC-AC) and neurons (hiPSC-N). To visualize the physiological morphology of each cell type, we used fluorescent cell-specific markers and confocal microscopy. Permeation of fluorescent solutes with different molecular weights was measured to demonstrate that the developed BBB was selectively permeable as a functional barrier

CD19 CAR T-cells for pediatric relapsed acute lymphoblastic leukemia with active CNS involvement: a retrospective international study

Relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) may occur in the central nervous system (CNS). Most clinical trials of CAR T-cell therapy excluded patients with active CNS leukemia, partially for concerns of neurotoxicity. Here, we report an international study of fifty-five children and adolescents who received CAR T-cell therapy for relapsed BCP-ALL with CNS involvement at the time of referral. All patients received bridging therapy, 16 still having active CNS disease at the time of lymphodepletion. Twelve patients received CD28-based CAR T-cells, 9 being subsequently treated with allogeneic hematopoietic stem-cell transplantation (allo-HSCT). Forty-three patients received 4-1BB-based CAR T-cells. Cytokine-release syndrome (CRS) and neurotoxicity occurred in 65% and 38% of patients, respectively, more frequently following treatment with CD28-based CARs. Fifty-one of 54 evaluable patients (94%) achieved complete response following this therapy. Relapse occurred in 22 patients: 19/43 following 4-1BB-based CARs (12 CNS relapses), and 3/12 after CD28-based CARs with subsequent HSCT (no CNS relapse). Patients treated with tisagenlecleucel for an isolated CNS relapse had a high incidence of a subsequent CNS relapse (6 of 8). CAR T-cells were found to be effective in this cohort, though the risk of CNS relapse was not completely mitigated by this approach