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Delayed immune reconstitution is a major challenge after matched unrelated donor (MUD) stem cell transplant (SCT). In this randomized phase 2 multi-center trial, Adoptive Immunotherapy with CD25/71 allodepleted donor T cells to improve immunity after unrelated donor stem cell transplant (NCT01827579), the authors tested whether allodepleted donor T cells (ADTs) can safely be used to improve immune reconstitution after alemtuzumab-based MUD SCT for hematological malignancies.Patients received standard of care or up to three escalating doses of ADTs generated through CD25+/CD71+ immunomagnetic depletion. The primary endpoint of the study was circulating CD3+ T-cell count at 4 months post-SCT. Twenty-one patients were treated, 13 in the ADT arm and eight in the control arm.The authors observed a trend toward improved CD3+ T-cell count at 4 months in the ADT arm versus the control arm (230/µL versus 145/µL, P = 0.18), and three ADT patients achieved normal CD3+ T-cell count at 4 months (700/µL). The rates of significant graft-versus-host disease (GVHD) were comparable in both cohorts, with grade ≥2 acute GVHD in seven of 13 and four of eight patients and chronic GVHD in three of 13 and three of eight patients in the ADT and control arms, respectively.These data suggest that adoptive transfer of ADTs is safe, but that in the MUD setting the benefit in terms of T-cell reconstitution is limited. This approach may be of more use in the context of more rigorous T-cell depletion.

Low-affinity CD19 chimeric antigen receptor (CAR) T cells display enhanced expansion and persistence, enabling fate tracking through integration site analysis. Here we show that integration sites from early (1 month) and late (>3yr) timepoints cluster separately, suggesting different clonal contribution to early responses and prolonged anti-leukemic surveillance. CAR T central and effector memory cells in patients with long-term persistence remained highly polyclonal, whereas diversity dropped rapidly in patients with limited CAR T persistence. Analysis of shared integrants between the CAR T cell product and post-infusion demonstrated that, despite their low frequency, T memory stem cell clones in the product contributed substantially to the circulating CAR T cell pools, during both early expansion and long-term persistence. Our data may help identify patients at risk of early loss of CAR T cells and highlight the critical role of T memory stem cells both in mediating early anti-leukemic responses and in long-term surveillance by CAR T cells.

BackgroundSchool meal programs have a large reach and thus are ideal environments in which to implement interventions targeting improved youth eating behaviors and reduced food waste. This systematic review summarizes the evidence on the effectiveness of school meal nudge interventions on influencing children’s eating and waste behaviors.MethodsInclusion criteria required studies have participants in primary or secondary school (grades K-12) with interventions that occurred during school lunch or breakfast in the cafeteria and included at least one of the following outcomes: selection, consumption, waste, or school meal participation. Analyses of intervention outcomes were restricted to studies of strong and moderate quality.ResultsTwenty-nine studies were included in the quality assessment. Included interventions fell into three categories: 1) placement/convenience, 2) marketing/promotion, or 3) variety/portions. The 20 strong and moderate quality studies included in outcome analyses generally used strong data collection methods and study designs, but were limited by an overall lack of intervention fidelity checks. Multi-component interventions often did not use methods that allowed for separate analyses of outcomes for different intervention components.ConclusionsSchool meal nudge interventions were positively associated with food selection, and had an inconsistent relationship with food consumption. There were few studies evaluating the impact of nudge interventions on meal participation or food waste. The limited evidence available links nudges to improved meal participation, as well as undesirable increases in food waste. Future research in this area should use methods that incorporate implementation metrics, attend to systems factors, and allow the outcomes of individual intervention components to be isolated.

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)1–5, but toxicity, including cytokine-release syndrome (CRS) and neurotoxicity, limits broader application. Moreover, 40–60% of patients relapse owing to poor CAR T cell persistence or emergence of CD19− clones. Some factors, including the choice of single-chain spacer6 and extracellular7 and costimulatory domains8, have a profound effect on CAR T cell function and persistence. However, little is known about the impact of CAR binding affinity. There is evidence of a ceiling above which increased immunoreceptor affinity may adversely affect T cell responses9–11. We generated a novel CD19 CAR (CAT) with a lower affinity than FMC63, the high-affinity binder used in many clinical studies1–4. CAT CAR T cells showed increased proliferation and cytotoxicity in vitro and had enhanced proliferative and in vivo antitumor activity compared with FMC63 CAR T cells. In a clinical study (CARPALL, NCT02443831 ), 12/14 patients with relapsed/refractory pediatric B cell acute lymphoblastic leukemia treated with CAT CAR T cells achieved molecular remission. Persistence was demonstrated in 11 of 14 patients at last follow-up, with enhanced CAR T cell expansion compared with published data. Toxicity was low, with no severe CRS. One-year overall and event-free survival were 63% and 46%, respectively. New low-affinity anti-CD19 CAR T cells exhibit peripheral expansion and persistence without inducing severe cytokine-response syndrome in pediatric patients with relapsed or refractory B cell acute lymphoblastic leukemia.

Frontal impacts with reclined occupants are rare but severe, and they are anticipated to become more common with the introduction of vehicles with automated driving capabilities. Computational and physical human surrogates are needed to design and evaluate injury countermeasures for reclined occupants, but the validity of such surrogates in a reclined posture is unknown. Experiments with post-mortem human subjects (PMHS) in a recline posture are needed both to define biofidelity targets for other surrogates and to describe the biomechanical response of reclined occupants in restrained frontal impacts. The goal of this study was to evaluate the kinematic and injury response of reclined PMHS in 30 g, 50 km/h frontal sled tests. Five midsize adult male PMHS were tested. A simplified semi-rigid seat with an anti-submarining pan and a non-production threepoint seatbelt (pre-tensioned, force-limited, seat-integrated) were used. Global motions and local accelerations of the head, pelvis, and multiple vertebrae were measured. Seat and seatbelt forces were also measured. Injuries were assessed via post-test dissection. The initial reclined posture aligned body regions (pelvis, lumbar spine, and ribcage) in a way that reduced the likelihood of effective restraint by the seat and seatbelt: the occupant's pelvis was initially rotated posteriorly, priming the occupant for submarining, and the lumbar spine was loaded in combined compression and bending due to the inertia of the upper torso during forward excursion. Coupled with the high restraining forces of the seat and seatbelt, the unfavorable kinematics resulted in injuries of the sacrum/coccyx (four of five PMHS injured), iliac wing (two of five PMHS injured), lumbar spine (three of five PMHS injured), and ribcage (all five PMHS suffered sternal fractures, and three of five PMHS suffered seven or more rib fractures). The kinematic and injury outcomes strongly motivate the development of injury criteria for the lumbar spine and pelvis, the inclusion of intrinsic variability (e.g., abdomen depth and pelvis shape) in computational simulations of frontal impacts with reclined occupants, and the adaptation of comprehensive restraint paradigms to predicted variability of occupant posture.

Highly automated vehicles may permit alternative seating postures, which could alter occupant kinematics and challenge current restraint designs. One predicted posture is a reclined seated position. While the spine of upright occupants is subjected to flexion during frontal crashes, the orientation of reclined occupants tends to subject the spine to high compressive loads followed by high flexion loads. This study aims to investigate kinematics and mechanisms of loading in the thoracolumbar spine for a reclined seated posture through the use of postmortem human subjects (PMHS). Frontal impact sled tests (50 kph delta-v) were conducted on five adult midsize male PMHS seated with the torso reclined to 50 degrees with respect to the vertical. The PMHS were seated on a semi-rigid seat and restrained by a seat-integrated three-point belt with dual lap-belt pretensioners and a shoulder-belt pretensioner with a 3 kN load-limiter. 3-D kinematic trajectories of five chosen vertebrae, and the pelvis were measured relative to the vehicle buck. Intervertebral pressure transducers were installed at three locations in the lumbar column to detect load timing. Three PMHS suffered fractures at L1. Combined compression and flexion of the thoracolumbar spine occurred in all tests, but the magnitude of peak flexion varied across the PMHS. During the PMHS' forward excursion, the pelvis rotated anteriorly in two tests and posteriorly in two tests (lap-belt submarining occurred in one). In one test, the pelvis mount interacted with the seat, but did not affect kinematics. Anterior rotation of the pelvis caused increased extension of the lumbar spine, which exacerbated lumbar compression in two of the PMHS; the one subject whose pelvis kinematic tracking was lost exhibited similar compression kinematics. Posterior rotation of the pelvis enabled lumbar flexion, which decreased lumbar compression, but lead to lap-belt submarining in one case. Lumbar kinematics for these reclined frontal impacts were sensitive to changes in initial posture of the spine (magnitude of lordosis or kyphosis) and pelvis (pitch angle). To our knowledge, this study is the first to analyze thoracolumbar kinematics and resulting injuries of a reclined seating posture using PMHS.

BACKGROUND: Kisspeptin is a key regulator of hypothalamic gonadotropin-releasing hormone (GnRH) neurons and is essential for reproductive health. A specific kisspeptin receptor (KISS1R) agonist could significantly expand the potential clinical utility of therapeutics targeting the kisspeptin pathway. Herein, we investigate the effects of a KISS1R agonist, MVT-602, in healthy women and in women with reproductive disorders. METHODS: We conducted in vivo and in vitro studies to characterize the action of MVT-602 in comparison with native kisspeptin-54 (KP54). We determined the pharmacokinetic and pharmacodynamic properties of MVT-602 (doses 0.01 and 0.03 nmol/kg) versus KP54 (9.6 nmol/kg) in the follicular phase of healthy women (n = 9), and in women with polycystic ovary syndrome (PCOS; n = 6) or hypothalamic amenorrhea (HA; n = 6). Further, we investigated their effects on KISS1R-mediated inositol monophosphate (IP(1)) and Ca(2+) signaling in cell lines and on action potential firing of GnRH neurons in brain slices. RESULTS: In healthy women, the amplitude of luteinizing hormone (LH) rise was similar to that after KP54, but peaked later (21.4 vs. 4.7 hours; P = 0.0002), with correspondingly increased AUC of LH exposure (169.0 vs. 38.5 IU∙h/L; P = 0.0058). LH increases following MVT-602 were similar in PCOS and healthy women, but advanced in HA (P = 0.004). In keeping with the clinical data, MVT-602 induced more potent signaling of KISS1R-mediated IP(1) accumulation and a longer duration of GnRH neuron firing than KP54 (115 vs. 55 minutes; P = 0.0012). CONCLUSION: Taken together, these clinical and mechanistic data identify MVT-602 as having considerable therapeutic potential for the treatment of female reproductive disorders. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) Registry, ISRCTN21681316. FUNDING: National Institute for Health Research and NIH.

Objective: Up to one-half of drivers swerve before a crash, which may cause vehicle motions that displace an occupant from a normal seated position. How these altered postures affect occupant restr...

Chimeric antigen receptor (CAR)-modified T cells targeting CD19 demonstrate unparalleled responses in relapsed/refractory acute lymphoblastic leukemia (ALL)

Objective: Self-driving technology will bring novelty in occupant seating choices and vehicle interior design. Thus, vehicle safety systems may be challenged to protect occupants over a wider range of potential postures and seating choices. This study aims to investigate the effects of occupant size, seat recline, and knee bolster position on submarining risk and injury prediction metrics for reclined occupants in frontal crashes. Methods: Frontal crash finite element (FE) simulations were performed with the 3 simplified Global Human Body Model Consortium (GHBMC) occupant models: small female, midsize male, and large male. Additionally, a detailed GHBMC midsize male model was used to compare with selected simplified cases. For each simulation, parameters including seatback recline angle (0.9°, 10.9°, 20.9°, 30.9°) and knee bolster position relative to the occupant (baseline, close, far, and no knee bolster) were varied. Impacts were simulated with the U.S. New Car Assessment Program 56 km/h frontal crash pulse. Occupant kinematics data were extracted from each simulation in a full-factorial sensitivity study to investigate how changes in anthropometry, seating position, and knee bolster position would affect submarining across all simulated cases. Results: Overall, increasing the occupant-to–knee bolster distance resulted in more submarining cases. The threshold for submarining was also affected by the seat recline angle. The lowest threshold observed occurred with 10.9° of recline with the small female model. Submarining was observed at recline angles at and above 20.9° for the midsize male model and 30° for the large male model. The initial lap belt position, pelvis orientation, and their relationship were good predictors of submarining. Increased lumbar flexion moment was observed with increased seat recline angle as well as occupant-to–knee bolster distance. The detailed GHBMC model was more prone to submarining than the simplified model. Conclusions: Submarining may be a major challenge to overcome for reclined occupants, which may become more prevalent with autonomous driving systems. This study shows that the angle of recline, anthropometric variation, and position of the knee bolster affect the risk of submarining. To our knowledge, this is the first study to computationally evaluate the occupant protection implications of seatback recline for multiple body sizes, postures, and positions relative to the vehicle interior.

Approximately 31% of food is lost or wasted at the retail and consumer levels in the U.S. Among consumers, young adults have been identified as one of the more wasteful segments of the population. In the U.S., many young adults (ages 18–24) attend a post-secondary education institution where they are often provided housing and meals through the college or university. Because of this, university dining facilities make an excellent target for food waste reduction strategies. The purpose of this study is to evaluate one food waste reduction strategy: changing the plate shape and size in university dining facilities. Specifically, this study compares individual food selection, consumption, and waste between round plates (9″ x 9″) and smaller oval platters (9.75″ x 7.75″) in a self-serve, all-you-care-to-eat dining environment. Compared to larger round plates, smaller oval platters significantly reduced average food selection (359.9 g vs. 318.0 g, P

Background There is interest in the use of very brief instruments to identify depression because of the advantages they offer in busy clinical settings. The PHQ-2, consisting of two questions relating to core symptoms of depression (low mood and loss of interest or pleasure), is one such instrument. Method A systematic review was conducted to identify studies that had assessed the diagnostic performance of the PHQ-2 to detect major depression. Embase, MEDLINE, PsychINFO and grey literature databases were searched. Reference lists of included studies and previous relevant reviews were also examined. Studies were included that used the standard scoring system of the PHQ-2, assessed its performance against a gold-standard diagnostic interview and reported data on its performance at the recommended (≥3) or an alternative cut-off point (≥2). After assessing heterogeneity, where appropriate, data from studies were combined using bivariate diagnostic meta-analysis to derive sensitivity, specificity, likelihood ratios and diagnostic odds ratios. Results 21 studies met inclusion criteria totalling N=11,175 people out of which 1529 had major depressive disorder according to a gold standard. 19 of the 21 included studies reported data for a cut-off point of ≥3. Pooled sensitivity was 0.76 (95% CI =0.68–0.82), pooled specificity was 0.87 (95% CI =0.82–0.90). However there was substantial heterogeneity at this cut-off (I2=81.8%). 17 studies reported data on the performance of the measure at cut-off point ≥2. Heterogeneity was I2=43.2% pooled sensitivity at this cut-off point was 0.91 (95% CI =0.85–0.94), and pooled specificity was 0.70 (95% CI =0.64–0.76). Conclusion The generally lower sensitivity of the PHQ-2 at cut-off ≥3 than the original validation study (0.83) suggests that ≥2 may be preferable if clinicians want to ensure that few cases of depression are missed. However, in situations in which the prevalence of depression is low, this may result in an unacceptably high false-positive rate because of the associated modest specificity. These results, however, need to be interpreted with caution given the possibility of selectively reported cut-offs.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: Our primary objective is to examine mental health and well‐being, mental health service usage, and adverse effects of Mental Health First Aid (MHFA) training on recipients of the intervention. We have three secondary objectives: 1. To examine the effects of MHFA training on recipients of the trainees' intervention, in terms of their knowledge about mental health and attitudes towards mental health problems. 2. To examine the effects of MHFA training on trainees' knowledge about mental health, attitudes towards mental health problems, number of encounters with people with mental health problems, and their own mental health and well‐being. 3. To examine the effects on organisations, looking at measures of absenteeism and productivity at work.

Objective: Recreational off-highway vehicle (ROHV) crashes are of concern because sales of these vehicles have been growing rapidly and because newer vehicles tend to have significantly greater performance than older models. We evaluated the available data to understand trends in ROHV crashes and the factors that contributed to serious injury. Methods: We combined information from (1) the Fatality Analysis Reporting System (FARS), (2) a database compiled by the Consumer Product Safety Commission, and (3) a vehicle sales database. These aggregated data were used to describe trends, demographics, and frequent causes of serious injuries and fatalities. Results: On-road fatal crashes grew from 0 in the year 2000 to 37 in 2015; at the same time, sales grew from approximately 100,000 to 400,000 vehicles annually. Much of the increase in ROHV sales was in 2 new, higher performance classes of vehicles. Further, seat belt and helmet use in this cohort was rare (at least 46% unbelted, only 2% confirmed to be helmeted) and drinking and driving was common (57% of crashes in FARS). These vehicles appear to have increased potential for rollover, which often led unbelted occupants to be ejected, putting them at risk of being injured as the vehicle rolled on top of them. Conclusions: Serious ROHV crashes have grown with sales. Resulting injuries appear to be strongly influenced by inconsistent seat belt use, frequent drunk driving, and increased propensity for the vehicles to roll over.

BackgroundThere is policy interest in the screening and treatment of mental health problems in young people who offend, but the value of such screening is not yet known.ObjectivesTo assess the diagnostic test accuracy of screening measures for mental health problems in young people who offend; to evaluate the clinical effectiveness and cost-effectiveness of screening and treatment; to model estimates of cost; to assess the evidence base for screening against UK National Screening Committee criteria; and to identify future research priorities.Data sourcesIn total, 25 electronic databases including MEDLINE, PsycINFO, EMBASE and The Cochrane Library were searched from inception until April 2011. Reverse citation searches of included studies were undertaken and reference list of included studies were examined.Review methodsTwo reviewers independently examined titles and abstracts and extracted data from included studies using a standardised form. The inclusion criteria for the review were (1) population – young offenders (aged 10–21 years); (2) intervention/instrument – screening instruments for mental health problems, implementation of a screening programme or a psychological or pharmacological intervention as part of a clinical trial; (3) comparator – for diagnostic test accuracy studies, any standardised diagnostic interview; for trials, any comparator; (4) outcomes – details of diagnostic test accuracy, mental health outcomes over the short or longer term or measurement of cost data; and (5) study design – for diagnostic test accuracy studies, any design; for screening programmes, randomised controlled trials or controlled trials; for clinical effectiveness studies, randomised controlled trials; for economic studies, economic evaluations of screening strategies or interventions.ResultsOf 13,580 studies identified, nine, including eight independent samples, met the inclusion criteria for the diagnostic test accuracy and validity of screening measures review. Screening accuracy was typically modest. No studies examined the clinical effectiveness of screening, although 10 studies were identified that examined the clinical effectiveness of interventions for mental health problems. There were too few studies to make firm conclusions about the clinical effectiveness of treatments in this population. No studies met the inclusion criteria for the assessment of the cost-effectiveness of screening or treatment. An exemplar decision model was developed for depression, which identified a number of the likely key drivers of uncertainty, including the prevalence of unidentified mental health problems, the severity of mental health problems and their relationship to generic measures of outcome and the impact of treatment on recidivism. The information evaluated as part of the review was relevant to five of the UK National Screening Committee criteria. On the basis of the above results, none of the five criteria was met.LimitationsThe conclusions of the review are based on limited evidence. Conclusions are tentative and the decision model should be treated as an exemplar.ConclusionsEvidence on the clinical effectiveness and cost-effectiveness of screening for mental health problems in young people who offend is currently lacking. Future research should consider feasibility trials of clinical interventions to establish important parameters ahead of conducting definitive trials. Future diagnostic studies should compare the diagnostic test accuracy of a range of screening instruments, including those recommended for use in the UK in this population. These studies should be designed to reduce the decision uncertainty identified by the exemplar decision model.RegistrationThis study is registered as PROSPERO CRD42011001466.FundingThe National Institute for Health Research Health Technology Assessment programme.

The arterial roots are important transitional regions of the heart, connecting the intrapericardial components of the aortic and pulmonary trunks with their ventricular outlets. They house the arterial (semilunar) valves and, in the case of the aorta, are the points of coronary arterial attachment. Moreover, because of the semilunar attachments of the valve leaflets, the arterial roots span the anatomic ventriculo‐arterial junction. By virtue of this arrangement, the interleaflet triangles, despite being fibrous, are found on the ventricular aspect of the root and located within the left ventricular cavity. Malformations and diseases of the aortic root are common and serious. Despite the mouse being the animal model of choice for studying cardiac development, few studies have examined the structure of their arterial roots. As a consequence, our understanding of their formation and maturation is incomplete. We set out to clarify the anatomical and histological features of the mouse arterial roots, particularly focusing on their walls and the points of attachment of the valve leaflets. We then sought to determine the embryonic lineage relationships between these tissues, as a forerunner to understanding how they form and mature over time. Using histological stains and immunohistochemistry, we show that the walls of the mouse arterial roots show a gradual transition, with smooth muscle cells (SMC) forming the bulk of wall at the most distal points of attachments of the valve leaflets, while being entirely fibrous at their base. Although the interleaflet triangles lie within the ventricular chambers, we show that they are histologically indistinguishable from the arterial sinus walls until the end of gestation. Differences become apparent after birth, and are only completed by postnatal day 21. Using Cre‐lox‐based lineage tracing technology to label progenitor populations, we show that the SMC and fibrous tissue within the walls of the mature arterial roots share a common origin from the second heart field (SHF) and exclude trans‐differentiation of myocardium as a source for the interleaflet triangle fibrous tissues. Moreover, we show that the attachment points of the leaflets to the walls, like the leaflets themselves, are derived from the outflow cushions, having contributions from both SHF‐derived endothelial cells and neural crest cells. Our data thus show that the arterial roots in the mouse heart are similar to the features described in the human heart. They provide a framework for understanding complex lesions and diseases affecting the aortic root.

Introduction: The CARPALL study (NCT02443831) employed a novel CD19CAR (CAT-41BBz CAR) with a faster off rate than the Kymriah FMC63-41BBz CAR (CAT 3.1x10-3s-1, FMC 6.8 x 10-5s-1), with equivalent on-rate (CAT 2.2 x 105, FMC 2.1 x 105). We herein report updated outcomes and CAR T cell persistence with an additional 6 months follow up from a submitted manuscript (Ghorashian et al., Nat Med, submitted) Methods: Patients aged CAT-41BBz CAR T cells were generated by magnetic bead activation of leucapheresed PBMCs, lentiviral transduction, followed by bioreactor expansion and magnetic bead removal prior to cryopreservation. All patients received lymphodepletion (fludarabine + cyclophosphamide) followed by 1x106/kg CAR T cells. Presence of CAR T cells in the blood and bone marrow (BM) was assessed (flow cytometry and qPCR) monthly for 6 months, then 6 weekly to 1 year and then 3 monthly. BM MRD was assessed (IgH qPCR, flow cytometry) at the same time-points up to 2 years to establish durability of responses as a stand-alone therapy. Primary end-points were incidence of grade 3-5 toxicity and the proportion of patients achieving molecular remission. Results: Of 17 patients recruited, 14 were treated due to manufacturing failure in 3 patients.The median age was 9 years (range 1-19 years). All patients had advanced ALL with a median of 4 prior therapy lines. 10 of 14 patients (71%) had relapsed post allogeneic SCT. Prior to lymphodepletion, 4 patients had >5% BM disease, 6 had disease between 5x10-2and 1x10-5, 4 were BM MRD negative having had recurrent isolated CNS disease. Median transduction efficiency was 31% (range 16.5 to 96.4%). 12/14 treated patients received the anticipated dose of 1x106CAR T cells/kg (2 received 0.9x106/kg). Considering all evaluable patients, (n=14 for CAR T cell persistence by qPCR, n=13 by flow) the geometric mean of Cmax was 128 912/µg DNA and of the area under the curve between D0 and D28 was 1,721,355 copies/ µg DNA (Table 1). At the point of maximal expansion, a median of 35% of circulating T cells were CAR+. Median half-life was 34 days (range 3-102). CAR T cells continued to be detectable by qPCR in 11 of 14 (79%) patients at last assessment and by flow cytometry up to 30 months post infusion in 8 of 13(61%). Median duration of CAR T persistence by flow was 261 days (range 7-917). 3 patients failed to have persistence of CAR T cells beyond 1 month. T cell mediated anti-CAR specific cytotoxic activity was detected in 2/2 evaluable patients. Updated persistence data will be presented at the meeting Cytokine release syndrome (CRS) occurred in 13 (93%, grade 1 n=9, grade 2 n=4). None developed ≥grade 3 CRS, had CRS-related ICU admission, or received Tocilizumab. CRS was associated with modest elevations of IL-6, IFN-γand IL-10. Grade 2 neurotoxicity was observed in 3 patients and resolved spontaneously. One patient had grade 4 leucoencephalopathy presumed due to chemotherapy as well as grade 5 sepsis. Ten patients (71%) had grade 3-4 cytopenia persisting beyond day 28 or recurring afterthis. 12/14 (86%) patients achieved molecular complete or continuing complete remission at a median of 30 days post infusion (range 30-90 days, Table 2). At a median follow-up of 20.3 months, 4/14 (29%) evaluable patients remain MRD negative. 5 relapsed with CD19-disease, 1 with CD19+ disease. The median duration of EFS (based on death or morphological relapse) has not been reached, 12 month EFS = 52%, OS = 70% (Figures 1, 2 and Table 3). Conclusion: We noted excellent CAR T cell expansion and persistence in a ALL cohort treated with the fast off-rate CAT-41BBz CAR despite their lower BM disease at treatment compared to other studies. The kinetics documented for all evaluable patients showed a 5-fold greater CAR T cell expansion and 2-fold longer half-life than responders in published series utilising tisagenlecleucel in a similar ALL cohort (Mueller et al., Blood 2017). Patients had a favourable toxicity profile with no severe (grade 3-4) CRS and equivalent disease outcomes to the ELIANA study despite having similarly advanced disease (Maude et al., NEJM 2018292). These data suggest long lived CAR T cell persistence supports stand-alone therapy for ALL with durable responses. Disclosures Ghorashian: Celgene: Honoraria; novartis: Honoraria; UCLB: Patents & Royalties: UCLB. Kramer:UCLB: Patents & Royalties. Ciocarlie:Servier: Other: Financial Support. Farzaneh:Autolus Ltd: Equity Ownership, Research Funding. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Amrolia:UCLB: Patents & Royalties.

Background:Patients with acute myeloid leukemia (AML), myelodysplasia (MDS) or tyrosine kinase inhibitor resistant chronic myeloid leukemia (CML) who are unsuitable for consolidative allogeneic stem cell transplantation (alloSCT) have high relapse rates following chemotherapy. Wilms' tumor 1 (WT1) is highly expressed in the majority of acute myeloid leukemias (AML) and in many subtypes of myelodysplasia (MDS) as well as other hematological and solid tumors. WT1 is an intracellular antigen, which makes it difficult to target using current Chimeric Antigen Receptor (CAR)-T cell technologies. The use of genetically modified T cells expressing WT1-specific α/β T cell receptors can re-direct T cell specificity via the recognition of intracellular peptides presented by MHC molecules on the malignant cell surface. Phase I clinical trials of WT1-TCR gene-modified T cells have been conducted in the settings of relapsed disease and post-alloSCT and preliminary data suggests this treatment approach is safe and potentially clinically effective in these cohorts (Tawara et al. Blood. 2017;130(18):1985-94; Chapuis et al, Nat Med. 2019;25(7):1064-72). Methods:We report a phase I/II safety and dose escalation study evaluating WT1-TCR gene-modified autologous T cells in HLA-A*0201 positive patients with AML, MDS and CML, unsuitable for alloSCT (NCT02550535) (Fig 1A). Patient T cells were harvested by leucapheresis and transduced with a retroviral vector construct encoding the codon optimised variable and constant a and bchains of the human pWT126-specific TCR separated by a self-cleaving 2A sequence (Fig 1B). Bulk transduced T cells were analysed by flow cytometry (CD3, CD8 and Vb2.1) prior to infusion and at regular intervals post-infusion. A quantitative PCR assay was developed to identify WT1-TCR expressing T cells in the peripheral blood post infusion. Patients received minimal conditioning with fludarabine and methylprednisolone prior to transfer of transduced T cells. All subjects were followed for a minimum of 12 months or until death. Results:A total of 10 patients (6 AML, 3 MDS and 1 TKI- resistant CML) were recruited. The mean age was 71.3 years (range 64-75) and all had high risk disease (by cytogenetic or clinical criteria). All AML patients were in complete morphological remission at the time of trial entry, whilst MDS patients had ≤ 15% blasts on bone marrow examination. All 10 patients received the gene-modified T cells in dose escalation cohorts (seven patients received £2x107/kg and three patients received £1x108/kg bulk WT1 TCR transduced cells). No adverse events directly attributable to the investigational product were recorded apart from one possible cytokine release syndrome, which was managed without tociluzimab. Transferred T cells demonstrated in vivoproliferation commensurate with maintenance of functional capacity despite ex vivo manipulation (Fig 1C and 1D). The TCR-transduced T cells were detectable in all patients at 28 days and in 7 patients persisted throughout the study period (Fig 1E). All 6 AML patients were alive at last follow up (median 12 months; range 7-12.8 months). The 3 patients with MDS had a median survival of 3 months (range 2.1-3.96 months) post T cell infusion. 2 died from progressive disease and one from other causes. 2 patients discontinued the study early due to disease progression. Conclusions: This is the second reported phase I/II clinical trial of autologous WT1-TCR gene-modified T cells for treatment of AML and MDS in a high-risk cohort of patients not suitable for alloSCT. We have shown that the WT1-TCR T cells demonstrated a strong safety profile without detectable on-target, off-tumour toxicity and no severe adverse events in the ten patients treated. An important cause of treatment failure for adoptive cellular therapies is the lack of persistence of transferred T cells leading to loss of disease specific effects. We demonstrated that autologous WT1-TCR T cells proliferated in vivoand persisted for many months. Recent work within our group (in press) has shown that TCRs modified to include key framework residues, show increased TCR expression and functional improvement. These modifications could be incorporated into future studies to improve efficacy. This data supports the rationale for a larger, phase II trial of WT1-TCR T cells in myeloid malignancies in patients for whom alloSCT is not appropriate, in order to assess clinical efficacy. Figure 1 Disclosures Morris: Quell Therapeutics: Consultancy, Other: Scientific Founder,stock; Orchard Therapeutics: Consultancy. Qasim:CellMedica: Research Funding; Bellicum: Research Funding; UCLB: Other: revenue share eligibility; Autolus: Equity Ownership; Orchard Therapeutics: Equity Ownership; Servier: Research Funding. Mount:Gamma Delta Therapeutics: Employment. Inman:Cellmedica: Employment. Gunter:Cellmedica: Employment. Stauss:Cell Medica: Other: I have stock; Quell Therapeutics: Consultancy, Other: I have stock.

Karl S Peggs and Sarah J Albon contributed equally to the work and are joint first author Introduction Alemtuzumab reduces the incidence of GVHD after unrelated donor stem cell transplant (MUD SCT) but delays immune reconstitution resulting in high morbidity/mortality from viral infections. Previous studies have suggested that adoptive transfer of allodepleted donor T cells (ADTs) improves immunity after SCT but this has never been tested in a randomised study. We developed a methodology for selective immunomagnetic depletion of alloreactive T-cells upregulating CD25 and CD71 after activation with host dendritic cells (DC) and showed that ADTs retain anti-viral responses with minimal host alloreactivity (Samarasinghe et al Blood 2010). We have now tested whether ADTs can safely be used to improve immune reconstitution after MUD SCT for haematological malignancies in a randomised Phase II multi-centre clinical study; ICAT (NCT01827579). Methods Patients undergoing Alemtuzumab-based peripheral blood SCT from a 9/10 or 10/10 MUD for haematological malignancy were randomised 2:1 to receive either the ATIMP (ADTs) or standard of care. Two weeks prior to SCT, patients randomised to ATIMP underwent a leucapheresis from which DCs were generated. Irradiated patient-derived DCs were then co-cultured with peripheral blood mononuclear cells (PBMC) from an unstimulated leucapheresis/500ml blood draw from the donor to activate alloreactive T cells. Four days later, the co-culture was depleted of CD25+ and CD71+ fractions by immunomagnetic depletion on the CliniMACs, sampled for residual alloreactivity and sterility, and cryopreserved. Patients randomised to the ATIMP were scheduled to receive 3 escalating doses of ADTs (0.1x106/Kg at day 30, 0.3x106/Kg at day 60 and 1x106/Kg at day 90 post-SCT) until either there was >grade 1 aGVHD or they had normal circulating T cells (>700/µL). The primary end-point of the study was circulating CD3+ T cell count at 4 months post-SCT with one-sided 15% significance level. Acute/chronic GVHD were graded using the Seattle/NIH criteria respectively. Results Twenty one patients were treated, 13 on the ATIMP arm and 8 on the control arm. The median age was 53 years and 67% (14) were male. 12 were AML/Myelodysplasia, 5 NHL, 3 CLL/CML and 1 HL. The median follow-up time is 14 months. Five of 13 ATIMP patients received 1 dose of ADTs, 4/13 2 doses and 4/13 all 3 doses. The incidence of acute and chronic GVHD was comparable between the arms. Overall, 7/13 ATIMP patients developed significant (>Grade 2) acute GVHD compared to 4/8 of the control arm (p>0.99). 3/13 patients in the ATIMP arm and 2/8 patients in the control arm developed severe aGVHD (all Grade 3). Three of 13 ATIMP cohort patients developed chronic GVHD (1 mild, 1 moderate, 1 severe), compared to 3/8 (all mild) in the control cohort. At 4 months, the circulating CD3+ T cell count mean was 730/µL (range 10-4080) in the ATIMP group and 212.5/µL (range 10-500) in the control group (1-sided p=0.11). However, the data was not normally distributed (Wilcoxon 1-sided p=0.18). Three ATIMP patients had high CD3+ T cell count at 4 months (>1000/µL). At 6 months, the mean circulating CD3+ T cell count was 833.6/µL (range 20-2690) and 327.5/µL (range 10-860). At month 4, the mean PHA stimulation index in the ATIMP arm was 16.8 (range 0.67- 73.1) vs 3.8 (range 1.1-8.2) in the control group. At 4 and 6 months post-SCT, spectratyping analysis showed no evidence of a difference in Vβ diversity between the 2 arms in both CD4+ and CD8+ cells. The 1-year survival rate in the ATIMP cohort is 92% vs 88% in the control, and 1-year disease free survival rate 67% in the ATIMP cohort vs 70% in the control. Conclusions These data suggest that adoptive transfer of ADTs improves T cell reconstitution in some patients after MUD SCT and that the GVHD rates were similar between ATIMP and control groups. Figure 1: Kinetics of T cell recovery after transplant in ATIMP (blue) and Control (red) patients. Mean +/- SEM shown. Figure 1 Disclosures Peggs: Gilead: Consultancy, Speakers Bureau; Autolus: Membership on an entity's Board of Directors or advisory committees. Ghorashian:UCLB: Patents & Royalties: UCLB; Celgene: Honoraria; novartis: Honoraria. Amrolia:UCLB: Patents & Royalties.

The aim of this study was to examine the value and benefits obtained from a semester length academic exchange for Australian early childhood teacher education students in equivalent programs in selected European sites. The data obtained from interviews conducted in this qualitative study indicate that students involved in the international mobility program experienced changes to their own sense of identity and their perception of other cultural practices and attitudes. In particular, the students' international experiences caused them to reflect deeply on matters of early childhood practice in their host and home countries and these reflections led, in some cases, to reconsiderations of their future role as practitioners. The students' reflections also offer the university sector some points to consider with respect to student mobility programs, particularly in how participants are supported in interpreting their overseas experience.

An effective therapeutic vaccine for the treatment of chronic hepatitis C virus (HCV) infection, as an adjunct to newly developed directly-acting antivirals (DAA), or for the prevention of reinfection would significantly reduce the global burden of disease associated with chronic HCV infection. A recombinant chimpanzee adenoviral (ChAd3) vector and a modified vaccinia Ankara (MVA), encoding the non-structural proteins of HCV (NSmut), used in a heterologous prime/boost regimen induced multi-specific, high-magnitude, durable HCV-specific CD4+ and CD8+ T-cell responses in healthy volunteers, and was more immunogenic than a heterologous Ad regimen. We now assess the immunogenicity of this vaccine regimen in HCV infected patients (including patients with a low viral load suppressed with Interferon/ribavirin therapy), determine T-cell cross-reactivity to endogenous virus, and compare immunogenicity with that observed previously in both healthy volunteers and in HCV infected patients vaccinated the heterologous Ad regimen. Vaccination of HCV infected patients with ChAd3-NSmut/MVA-NSmut was well tolerated. Vaccine-induced HCV-specific T-cell responses were detected in 8/12 patients; however, CD4+ T- cell responses were rarely detected, and overall the magnitude of HCV-specific T-cell responses was markedly reduced when compared to vaccinated healthy volunteers. Furthermore, HCV specific cells had a distinct partially-functional phenotype (lower expression of activation markers, granzyme B, and TNFa production, weaker in vitro proliferation, and higher Tim3 expression, with comparable Tbet and Eomes expression) compared to healthy volunteers. Robust anti-vector T-cells and antibodies were induced showing that there is no global defect in immunity. The level of viremia at the time of vaccination did not correlate with the magnitude of the vaccine-induced T- cell response. Full-length, next generation sequencing of circulating virus demonstrated that T-cells were only induced by vaccination when there was sequence mismatch between autologous virus and the vaccine immunogen. However, these T cells were not cross -reactive with endogenous viral variant epitopes. Conversely when there was complete homology between immunogen and circulating virus at a given epitope T-cells were not induced. T-cell induction following vaccination had no significant impact on HCV viral load. In vitro T-cell culture experiments identified the presence of T-cells at baseline that could be expanded by vaccination; thus HCV-specific T-cells may have been expanded from pre-existing low-level memory T-cell populations that had been exposed to HCV antigen during natural infection, explaining the partial T-cell dysfunction. In conclusion, vaccination with ChAd3-NSmut and MVA-NSmut prime/boost, a potent vaccine regimen previously optimised in healthy volunteers, was unable to reconstitute HCV-specific T-cell immunity in HCV infected patients. This highlights the major challenge of overcoming T-cell exhaustion in the context of persistent antigen exposure.

Introduction: Published studies of CD19 CAR T cells have shown unprecedented response rates in ALL but with a 23-27% incidence of severe Cytokine Release Syndrome (CRS) and 27-50% incidence of severe neurotoxicity which may limit broader application. We developed a novel second generation CD19CAR (CAT-41BBz CAR) with a lower affinity and faster off-rate but equivalent on-rate than the FMC63-41BBz CAR (Kd 116 nM vs 0.9 nM, T1/2 10s vs 1260s) utilised in CTL019 currently under consideration by the FDA. Pre-clinical studies indicated T-cells transduced with CAT-41BBz mediate enhanced tumor clearance and show increased expansion in an NSG-NALM6 stress test model (Kramer et al., submitted). We here report interim results from a multi-centre, Phase I clinical study of autologous CAT-41BBz CAR T cells as therapy for high risk/relapsed paediatric ALL, CARPALL (NCT02443831) demonstrating efficacy with an excellent safety profile. Methods: Autologous T cells were activated with anti-CD3/CD28 beads, transduced with a SIN lentiviral vector encoding CAT-41BBz CAR and expanded for 4 days prior to magnetic bead removal and cryopreservation. Transduction efficiency was assessed using an anti-idiotype antibody. Serum levels of cytokines associated with CRS were measured using cytometric bead array. All patients received lymphodepletion with fludarabine 150 mg/m2 + cyclophosphamide 1.5g/m2 followed by a single infusion of CAR T cells at a dose of 1x106 CAR+ T cells. Patients were monitored for the presence of CAR T cells in the blood by flow cytometry and by qPCR for the 41BBz junctional region, as well as circulating B cell count monthly for 6 months and then 6 weekly to 1 year. Disease status was assessed in the bone marrow morphologically, by IgH qPCR, as well as by flow cytometric assessment of MRD at the same time-points to establish durability of responses as a stand-alone therapy. The primary end-points were incidence of grade 3-5 toxicity related to CAR T cells within 30 days and the proportion of patients achieving molecular remission. Results: We have enrolled 10 patients and treated 8 to date. Six of 8 had relapsed post myeloablative SCT. The median disease burden prior to lymphodepletion was 9% blasts (ranging from molecular CR to 74% blasts, Table 1). It was possible to generate a product meeting release criteria in all but 1 patient (90% feasibility). Median transduction efficiency was 18.1% (range 6.7 to 76.3%). All treated patients received the anticipated dose of 1x106 CAR T cells/kg. Cytokine release syndrome occurred in all patients (grade 1 n=4, grade 2 n=4), but to date none have developed ≥ grade 3 CRS, required ICU admission or therapy with Tocilizumab. CRS was associated with modest elevations of IL-6, IFN-γ and IL-10 and resolved spontaneously in all. Grade 2 neurotoxicity was observed in 3 patients and resolved spontaneously, but no severe (≥grade 3) neurotoxicity was seen. Five patients had prolonged grade 4 neutropenia lasting > 30 days but this resolved in all by 2 months. Only 1 patient experienced significant infective complications in the context of pre-existing poor marrow reserve following allogeneic SCT. 6/7 (86%) evaluable patients achieved molecular remission at a median of 30 days post infusion (range 30-60 days, Table 1). One patient did not respond and died of CD19+ disease progression. At a median follow-up of 5.9 months (range 28-328 days), 4/7 evaluable patients remain in flow MRD negative remission of whom 3 show no evidence of molecular MRD at 1, 7.5 and 9 months. Two patients relapsed with CD19- disease at 3 and 4 months post infusion: 1 of these remains alive with disease at 11 months and the other died of disease progression. Reflecting our pre-clinical data with CAT-41BBz CAR, we have seen excellent CAR T cell expansion (median 65459 copies/µg DNA at 1 month, range 609 to 230112) and persistence at up to 11 months post-infusion (Figure 1). All 7 evaluable patients have ongoing CAR T cell persistence detectable by both flow and qPCR as well as ongoing B cell aplasia at last follow-up. Conclusions: These interim results with a novel low affinity CD19 CAR show similar remission rates to those reported by US studies in paediatric ALL with an improved safety profile. No severe (grade ≥3) CRS or neurotoxicity has occurred to date despite high tumour burden in 4 patients. Excellent CAR T cell expansion has been documented, as well as long duration of CAR T cell persistence and associated B cell aplasia. Disclosures Ghorashian: UCL: Patents & Royalties: UCL Business. Kramer: UCL: Patents & Royalties: UCL Business. Lucchini: Alexion: Membership on an entity's Board of Directors or advisory committees. Pule: Autolus Ltd: Employment, Equity Ownership, Research Funding; UCL: Patents & Royalties: UCL Business.

This study evaluated the hypothesis that upper extremity function and range of motion can be quantified reliably in children with cerebral palsy (CP) in a busy clinical setting. The specific aim was to determine the inter- and intrarater reliability of a modified House Functional Classification (MHC) system to evaluate upper extremity function and a standardized instrument to document upper extremity range of motion (Upper Extremity Rating Scale [UERS]). Sixty-five children with CP (43 males, 22 females, mean age 9y 2mo, SD 4y 1mo) with spasticity involving the upper extremity (quadriplegia n=22; hemiplegia n=36; diplegia n=7; Gross Motor Functional Classification System Levels I n=41, II n=6, III n=3, IV n=5, V n=10) were evaluated independently by occupational therapists and orthopedic surgeons using both instruments at several visits. Inter- and intrarater reliability were determined for both instruments by calculating measures of agreement (weighted kappa values and intraclass correlation coefficients [ICCs]). Interrater agreement (ICC=0.94) and intrarater agreement (ICC=0.96) on the MHC were good to excellent. Similarly, inter-rater agreement (kappa 0.66-0.81) and intrarater agreement (kappa 0.64-0.88) on the UERS was either good or excellent. The MHC and the UERS provide standardized, reliable, reproducible, and efficient instruments that can be used by occupational therapists and orthopedic surgeons to evaluate the upper extremities of children with CP.

Background: There has been little research into self-help books for people with depression, despite the apparent plethora of such titles. As an initial step, we undertook a scoping review of availa...

BackgroundComputerised cognitive behaviour therapy (cCBT) has been developed as an efficient form of therapy delivery with the potential to enhance access to psychological care. Independent research is needed which examines both the clinical effectiveness and cost-effectiveness of cCBT over the short and longer term.ObjectivesTo compare the clinical effectiveness and cost-effectiveness of cCBT as an adjunct to usual general practitioner (GP) care against usual GP care alone, for a free-to-use cCBT program (MoodGYM; National Institute for Mental Health Research, Australian National University, Canberra, Australia) and a commercial pay-to-use cCBT program (Beating the Blues®; Ultrasis, London, UK) for adults with depression, and to determine the acceptability of cCBT and the experiences of users.DesignA pragmatic, multicentre, three-armed, parallel, randomised controlled trial (RCT) with concurrent economic and qualitative evaluations. Simple randomisation was used. Participants and researchers were not blind to treatment allocation.SettingPrimary care in England.ParticipantsAdults with depression who scored ≥ 10 on the Patient Health Questionnaire-9 (PHQ-9).InterventionsParticipants who were randomised to either of the two intervention groups received cCBT (Beating the Blues or MoodGYM) in addition to usual GP care. Participants who were randomised to the control group were offered usual GP care.Main outcome measuresThe primary outcome was depression at 4 months (PHQ-9). Secondary outcomes were depression at 12 and 24 months; measures of mental health and health-related quality of life at 4, 12 and 24 months; treatment preference; and the acceptability of cCBT and experiences of users.ResultsClinical effectiveness:210 patients were randomised to Beating the Blues, 242 patients were randomised to MoodGYM and 239 patients were randomised to usual GP care (total 691). There was no difference in the primary outcome (depression measured at 4 months) either between Beating the Blues and usual GP care [odds ratio (OR) 1.19, 95% confidence interval (CI) 0.75 to 1.88] or between MoodGYM and usual GP care (OR 0.98, 95% CI 0.62 to 1.56). There was no overall difference across all time points for either intervention compared with usual GP care in a mixed model (Beating the Blues versus usual GP care,p = 0.96; and MoodGYM versus usual GP care,p = 0.11). However, a small but statistically significant difference between MoodGYM and usual GP care at 12 months was found (OR 0.56, 95% CI 0.34 to 0.93). Free-to-use cCBT (MoodGYM) was not inferior to pay-to-use cCBT (Beating the Blues) (OR 0.91, 90% CI 0.62 to 1.34;p = 0.69). There were no consistent benefits of either intervention when secondary outcomes were examined. There were no serious adverse events thought likely to be related to the trial intervention. Despite the provision of regular technical telephone support, there was low uptake of the cCBT programs.Cost-effectiveness:cost-effectiveness analyses suggest that neither Beating the Blues nor MoodGYM appeared cost-effective compared with usual GP care alone.Qualitative evaluation:participants were often demotivated to access the computer programs, by reason of depression. Some expressed the view that a greater level of therapeutic input would be needed to promote engagement.ConclusionsThe benefits that have previously been observed in developer-led trials were not found in this large pragmatic RCT. The benefits of cCBT when added to routine primary care were minimal, and uptake of this mode of therapy was relatively low. There remains a clinical and economic need for effective low-intensity psychological treatments for depression with improved patient engagement.Trial registrationThis trial is registered as ISRCTN91947481.FundingThis project was funded by the National Institute for Health Research Health Technology Assessment programme.

In the UK, recent guidelines on the treatment of depression and anxiety recommend CBT-based self-help materials as one important component of services. However, despite being based on specific CBT techniques or “empirically grounded interventions”, early optimism has been dented by data from recent studies that have cast doubt on the effectiveness of the current generation of these materials. As a consequence, it may be necessary to consider that other factors may contribute to the overall magnitude of CBT effects. Indeed, it is logically inconsistent to argue that specific factors are pre-eminent in CBT whilst maintaining that delivery via therapists is more likely to be effective than self-help. The contribution of “common factors” that operate in personal therapeutic encounters, for example, therapist responsiveness and the patient-therapist alliance, may be one possible overlooked reason for the reduced ef-fectiveness of self-help materials. The development of the next generation of self-help materials, therefore, may benefit from the testing of materials that combine common and specific factors, including specific measurement of the strength of common factors and their relationship to clinical outcomes. We discuss a model of such common factors and suggest how they could be incorporated into the next generation of CBT based self-help materials.