Pharmacogenetics of tenofovir drug transporters in the context of HBV: Is there an impact?

BACKGROUND: Current treatments for chronic hepatitis B management include orally administered nucleos(t)ide analogues, such as tenofovir (TDF), which is an acyclic adenine nucleotide analogue used both in HBV and human immune deficiency virus (HIV). The course of HBV infection is mainly dependent on viral factors, such as HBV genotypes, immunological features and host genetic variables, but a few data are available in the context of HBV, in particular for polymorphisms of genes encoding proteins involved in drug metabolism and elimination. Consequently, the aim of this study was to evaluate the potential impact of genetic variants on TDF plasma and urine concentrations in patients with HBV, considering the role of HBV genotypes. METHODS: A retrospective cohort study at the Infectious Disease Unit of Amedeo di Savoia Hospital, Torino, Italy, was performed. Pharmacokinetic analyses were performed through liquidi chromatography, whereas pharmacogenetic analyses through real-time PCR. FINDINGS: Sixty - eight patients were analyzed: ABCC4 4976 C>T genetic variant showed an impact on urine TDF drug concentrations (p = 0.014). In addition, SLC22A6 453 AA was retained in the final regression multivariate model considering factors predicting plasma concentrations, while ABCC4 4976 TC/CC was the only predictor of urine concentrations in the univariate model. INTERPRETATION: In conclusion, this is the first study showing a potential impact of genetic variants on TDF plasma and urine concentrations in the HBV context, but further studies in different and larger cohorts of patients are required.

Erratum: Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells.

[This corrects the article DOI: 10.1016/j.omto.2023.07.003.].

Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells.

Discrimination between hematopoietic stem cells and leukemic stem cells remains a major challenge for acute myeloid leukemia immunotherapy. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells before consolidation with allogeneic hematopoietic stem cell transplantation in absence of cytotoxic conditioning. Here we exploit non-viral technology to achieve early termination of CAR T cell activity to prevent incoming graft rejection. Transient expression of an anti-CD117 CAR by mRNA conferred T cells the ability to eliminate CD117+ targets in vitro and in vivo. As an alternative approach, we used a Sleeping Beauty transposon vector for the generation of CAR T cells incorporating an inducible Caspase 9 safety switch. Stable CAR expression was associated with high proportion of T memory stem cells, low levels of exhaustion markers, and potent cellular cytotoxicity. Anti-CD117 CAR T cells mediated depletion of leukemic cells and healthy hematopoietic stem cells in NSG mice reconstituted with human leukemia or CD34+ cord blood cells, respectively, and could be terminated in vivo. The use of a non-viral technology to control CAR T cell pharmacokinetic properties is attractive for a first-in-human study in patients with acute myeloid leukemia prior to hematopoietic stem cell transplantation.

Diagnostic performance of augmented intelligence with 2D and 3D total body photography and convolutional neural networks in a high-risk population for melanoma under real-world conditions: A new era of skin cancer screening?

BACKGROUND: Convolutional neural networks (CNNs) have outperformed dermatologists in classifying pigmented skin lesions under artificial conditions. We investigated, for the first time, the performance of three-dimensional (3D) and two-dimensional (2D) CNNs and dermatologists in the early detection of melanoma in a real-world setting. METHODS: In this prospective study, 1690 melanocytic lesions in 143 patients with high-risk criteria for melanoma were evaluated by dermatologists, 2D-FotoFinder-ATBM and 3D-Vectra WB360 total body photography (TBP). Excision was based on the dermatologists' dichotomous decision, an elevated CNN risk score (study-specific malignancy cut-off: FotoFinder >0.5, Vectra >5.0) and/or the second dermatologist's assessment with CNN support. The diagnostic accuracy of the 2D and 3D CNN classification was compared with that of the dermatologists and the augmented intelligence based on histopathology and dermatologists' assessment. Secondary end-points included reproducibility of risk scores and naevus counts per patient by medical staff (gold standard) compared to automated 3D and 2D TBP CNN counts. RESULTS: The sensitivity, specificity, and receiver operating characteristics area under the curve (ROC-AUC) for risk-score-assessments compared to histopathology of 3D-CNN with 95% confidence intervals (CI) were 90.0%, 64.6% and 0.92 (CI 0.85-1.00), respectively. While dermatologists and augmented intelligence achieved the same sensitivity (90%) and comparable classification ROC-AUC (0.91 [CI 0.80-1.00], 0.88 [CI 0.77-1.00]) with 3D-CNN, their specificity was superior (92.3% and 86.2%, respectively). The 2D-CNN (sensitivity: 70%, specificity: 40%, ROC-AUC: 0.68 [CI 0.46-0.90]) was outperformed by 3D CNN and dermatologists. The 3D-CNN showed a higher correlation coefficient for repeated measurements of 246 lesions (R = 0.89) than the 2D-CNN (R = 0.79). The mean naevus count per patient varied significantly (gold standard: 210 lesions; 3D-CNN: 469; 2D-CNN: 1324; p < 0.0001). CONCLUSIONS: Our study emphasises the importance of validating the classification of CNNs in real life. The novel 3D-CNN device outperformed the 2D-CNN and achieved comparable sensitivity with dermatologists. The low specificity of CNNs and the lack of automated counting of TBP nevi currently limit the use of augmented intelligence in clinical practice.

Astrocytes: Dissecting Their Diverse Roles in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders often co-occurring in the same patient, a feature that suggests a common origin of the two diseases. Consistently, pathological inclusions of the same proteins as well as mutations in the same genes can be identified in both ALS/FTD. Although many studies have described several disrupted pathways within neurons, glial cells are also regarded as crucial pathogenetic contributors in ALS/FTD. Here, we focus our attention on astrocytes, a heterogenous population of glial cells that perform several functions for optimal central nervous system homeostasis. Firstly, we discuss how post-mortem material from ALS/FTD patients supports astrocyte dysfunction around three pillars: neuroinflammation, abnormal protein aggregation, and atrophy/degeneration. Furthermore, we summarize current attempts at monitoring astrocyte functions in living patients using either novel imaging strategies or soluble biomarkers. We then address how astrocyte pathology is recapitulated in animal and cellular models of ALS/FTD and how we used these models both to understand the molecular mechanisms driving glial dysfunction and as platforms for pre-clinical testing of therapeutics. Finally, we present the current clinical trials for ALS/FTD, restricting our discussion to treatments that modulate astrocyte functions, directly or indirectly.

Institutional quality and COVID-19 vaccination: does decentralization matter?

Vaccination campaigns are one of the factors that can help mitigate the adverse effects of viral pandemics. The aim of this paper is to understand the institutional factors that are associated with a higher success rate, measured by the percentage of vaccinated population against COVID-19 across countries. Along with supply side determinants, institutional factors, related, at the national level, to the organization of the healthcare sector, governance and organization of the State and social capital, and, at the subnational level related to the authority and autonomy of lower tiers of government, are important correlates of successful vaccination campaigns, suggesting potential areas of public policy interventions.

Feasibility of Remote Unsupervised Cognitive Screening With SATURN in Older Adults.

Widespread cognitive test screening as part of tele-public health initiatives necessitates a test that is self-administered online and automatically scored, with no clinician effort. The feasibility of unsupervised cognitive screening is unclear. We adapted the Self-Administered Tasks Uncovering Risk of Neurodegeneration (SATURN) to make it suitable for self-administration and automatic scoring. A sample of 364 healthy older adults completed SATURN via a web browser, in a fully independent manner. SATURN's overall score was not modulated by gender, education, reading speed, the time of day at which the test was taken, or an individual's familiarity with technology. SATURN proved extremely portable across operating systems. Importantly, comments from participants reported satisfaction with the experience and the clarity of the instructions. SATURN represents a fast and easy screening tool that can be used for a first assessment, during a routine test or clinical evaluation, or during periodic health monitoring, in person or remotely.

IL-33 Induces an Antiviral Signature in Mast Cells but Enhances Their Permissiveness for Human Rhinovirus Infection.

Mast cells (MCs) are classically associated with allergic asthma but their role in antiviral immunity is unclear. Human rhinoviruses (HRVs) are a major cause of asthma exacerbations and can infect and replicate within MCs. The primary site of HRV infection is the airway epithelium and MCs localise to this site with increasing asthma severity. The asthma susceptibility gene, IL-33, encodes an epithelial-derived cytokine released following HRV infection but its impact on MC antiviral responses has yet to be determined. In this study we investigated the global response of LAD2 MCs to IL-33 stimulation using RNA sequencing and identified genes involved in antiviral immunity. In spite of this, IL-33 treatment increased permissiveness of MCs to HRV16 infection which, from the RNA-Seq data, we attributed to upregulation of ICAM1. Flow cytometric analysis confirmed an IL-33-dependent increase in ICAM1 surface expression as well as LDLR, the receptors used by major and minor group HRVs for cellular entry. Neutralisation of ICAM1 reduced the IL-33-dependent enhancement in HRV16 replication and release in both LAD2 MCs and cord blood derived MCs. These findings demonstrate that although IL-33 induces an antiviral signature in MCs, it also upregulates the receptors for HRV entry to enhance infection. This highlights the potential for a gene-environment interaction involving IL33 and HRV in MCs to contribute to virus-induced asthma exacerbations.

Sod translocation to restore habitats of the myrmecophilous butterfly Phengaris (Maculinea) teleius on former agricultural fields.

In Europe, 50%-70% of former natural grassland area has been destroyed during the past 30 years due to land use changes, losses are expected to increase in the future. Restoration is thought to reverse this situation by creating suitable abiotic conditions. In this paper, we investigate the effects of sod translocation with specific vegetation to facilitate the restoration of a former intensive agricultural field into a wet meadow. First, starting conditions were optimized including modification of the local hydrology, removal of the fertilized topsoil, application of liming, and translocation of fresh clippings as a seed source. The second part aimed at restoring the habitat for the butterfly species Phengaris (Maculinea) teleius, one of the species that was especially affected by the loss of wet meadows. This species engages in a complex myrmecophilous relationship with one host plant, Sanguisorba officinalis, and one obligate host ant, Myrmica scabrinodis. We used sod translocation to create islands of habitat to promote host plant and host ant colonization. After 4 years following the restoration, we observed that plants spread from the transplanted sods to the surroundings. The vegetation composition and structure of the transplanted sods attracted colonization of Myrmica ants into the restored areas. Following the increase in vegetation cover and height, Myrmica ant colonies further spread into the restored areas. Therefore, sod translocations can be considered an effective restoration method following topsoil removal in the process of restoring wet meadows to provide a starting point for ant colonization and plant dispersion. With these findings, this paper contributes to the evidence-based restoration of wet meadows on former agricultural fields, including complex interactions between invertebrates and their required ecological relationships.

The Past, Present, and Future of Non-Viral CAR T Cells.

Adoptive transfer of chimeric antigen receptor (CAR) T lymphocytes is a powerful technology that has revolutionized the way we conceive immunotherapy. The impressive clinical results of complete and prolonged response in refractory and relapsed diseases have shifted the landscape of treatment for hematological malignancies, particularly those of lymphoid origin, and opens up new possibilities for the treatment of solid neoplasms. However, the widening use of cell therapy is hampered by the accessibility to viral vectors that are commonly used for T cell transfection. In the era of messenger RNA (mRNA) vaccines and CRISPR/Cas (clustered regularly interspaced short palindromic repeat-CRISPR-associated) precise genome editing, novel and virus-free methods for T cell engineering are emerging as a more versatile, flexible, and sustainable alternative for next-generation CAR T cell manufacturing. Here, we discuss how the use of non-viral vectors can address some of the limitations of the viral methods of gene transfer and allow us to deliver genetic information in a stable, effective and straightforward manner. In particular, we address the main transposon systems such as Sleeping Beauty (SB) and piggyBac (PB), the utilization of mRNA, and innovative approaches of nanotechnology like Lipid-based and Polymer-based DNA nanocarriers and nanovectors. We also describe the most relevant preclinical data that have recently led to the use of non-viral gene therapy in emerging clinical trials, and the related safety and efficacy aspects. We will also provide practical considerations for future trials to enable successful and safe cell therapy with non-viral methods for CAR T cell generation.

Power shift and connectivity changes in healthy aging during resting-state EEG.

The neural activity of human brain changes in healthy individuals during aging. The most frequent variation in patterns of neural activity are a shift from posterior to anterior areas and a reduced asymmetry between hemispheres. These patterns are typically observed during task execution and by using functional magnetic resonance imaging data. In the present study we investigated whether analogous effects can also be detected during rest and by means of source-space time series reconstructed from electroencephalographic recordings. By analyzing oscillatory power distribution across the brain we indeed found a shift from posterior to anterior areas in older adults. We additionally examined this shift by evaluating connectivity and its changes with age. The findings indicated that inter-area connections among frontal, parietal and temporal areas were strengthened in older individuals. A more complex pattern was shown in intra-area connections, where age-related activity was enhanced in parietal and temporal areas, and reduced in frontal areas. Finally, the resulting network exhibits a loss of modularity with age. Overall, the results extend to resting-state condition the evidence of an age-related shift of brain activity from posterior to anterior areas, thus suggesting that this shift is a general feature of the aging brain rather than being task-specific. In addition, the connectivity results provide new information on the reorganization of resting-state brain activity in aging.

Influence of the solvent in the self-assembly and binding properties of [1 + 1] tetra-imine bis-calix[4]pyrrole cages.

We report the self-assembly of shape-persistent [1 + 1] tetra-imine cages 1 based on two different tetra-α aryl-extended calix[4]pyrrole scaffolds in chlorinated solvents and in a 9 : 1 CDCl3 : CD3CN solvent mixture. We show that the use of a bis-N-oxide 4 (4,4'-dipyridyl-N,N'-dioxide) as template is not mandatory to induce the emergence of the cages but has a positive effect on the reaction yield. We use 1H NMR spectroscopy to investigate and characterize the binding properties (kinetic and thermodynamic) of the self-assembled tetra-imine cages 1 with pyridine N-oxide derivatives. The cages form kinetically and thermodynamically stable inclusion complexes with the N-oxides. For the bis-N-oxide 4, we observe the exclusive formation of 1 : 1 complexes independently of the solvent used. In contrast, the pyridine-N-oxide 5 (mono-topic guest) produces inclusion complexes displaying solvent dependent stoichiometry. The bis-N-oxide 4 is too short to bridge the gap between the two endohedral polar binding sites of 1 by establishing eight ideal hydrogen bonding interactions. Nevertheless, the bimolecular 4⊂1 complex results as energetically favored compared to the 52⊂1 ternary counterpart. The inclusion of the N-oxides, 4 and 5, in the tetra-imine cages 1 is significantly faster in chlorinated solvents (minutes) than in the 9 : 1 CDCl3 : CD3CN solvent mixture (hours). We provide an explanation for the similar energy barriers calculated for the formation of the 4⊂1 complex using the two different ternary counterparts 52⊂1 and (CD3CN)2⊂1 as precursors. We propose a mechanism for the in-out guest exchange processes experienced by the tetra-imine cages 1.

What Can Neural Activity Tell Us About Cognitive Resources in Aging?

A reduction in cognitive resources has been originally proposed to account for age-related decrements in several cognitive domains. According to this view, aging limits the pool of available cognitive supplies: Compared to younger adults, elderly exhaust the resources more rapidly as task difficulty increases, hence a dramatic performance drop. Neurophysiological indexes (e.g., BOLD response and EEG activity) may be instrumental to quantify the amount of such cognitive resources in the brain and to pinpoint the stage of stimulus processing where the decrement in age-related resources is evident. However, as we discuss in this mini-review, the most recent studies on the neurophysiological markers of age-related changes lack a consistent coupling between neural and behavioral effects, which casts doubt on the advantage of measuring neural indexes to study resource deployment in aging. For instance, in the working memory (WM) domain, recent cross-sectional studies found varying patterns of concurrent age-related brain activity, ranging from equivalent to reduced and increased activations of old with respect to younger adults. In an attempt to reconcile these seemingly inconsistent findings of brain-behavior coupling, we focus on the contribution of confounding sources of variability and propose ways to control for them. Finally, we suggest an alternative perspective to explain age-related effects that implies a qualitative (instead of or along with a quantitative) difference in the deployment of cognitive resources in aging.

Contribution of RNA/DNA Binding Protein Dysfunction in Oligodendrocytes in the Pathogenesis of the Amyotrophic Lateral Sclerosis/Frontotemporal Lobar Degeneration Spectrum Diseases.

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders, often considered as the extreme manifestations of a disease spectrum, as they share similar pathomechanisms. In support of this, pathological aggregation of the RNA/DNA binding proteins trans-activation response element DNA-binding protein 43 (TDP-43) or fused in sarcoma (FUS) is the pathological hallmark found in neurons and glial cells of subsets of patients affected by either condition (i.e., ALS/FTLD-TDP-43 or ALS/FTLD-FUS, respectively). Among glia, oligodendrocytes are the most abundant population, designated to ensheath the axons with myelin and to provide them with metabolic and trophic support. In this minireview, we recapitulate the neuropathological evidence for oligodendroglia impairment in ALS/FTLD. We then debate how TDP-43 and FUS target oligodendrocyte transcripts, thereby controlling their homeostatic abilities toward the axons. Finally, we discuss cellular and animal models aimed at investigating the functional consequences of manipulating TDP-43 and FUS in oligodendrocytes in vivo. Taken together, current data provide increasing evidence for an important role of TDP-43 and FUS-mediated oligodendroglia dysfunction in the pathogenesis of ALS/FTLD. Thus, targeting disrupted oligodendroglial functions may represent a new treatment approach for these conditions.

Challenges and Opportunities of Targeting Astrocytes to Halt Neurodegenerative Disorders.

Neurodegenerative diseases are a heterogeneous group of disorders whose incidence is likely to duplicate in the next 30 years along with the progressive aging of the western population. Non-cell-specific therapeutics or therapeutics designed to tackle aberrant pathways within neurons failed to slow down or halt neurodegeneration. Yet, in the last few years, our knowledge of the importance of glial cells to maintain the central nervous system homeostasis in health conditions has increased exponentially, along with our awareness of their fundamental and multifaced role in pathological conditions. Among glial cells, astrocytes emerge as promising therapeutic targets in various neurodegenerative disorders. In this review, we present the latest evidence showing the astonishing level of specialization that astrocytes display to fulfill the demands of their neuronal partners as well as their plasticity upon injury. Then, we discuss the controversies that fuel the current debate on these cells. We tackle evidence of a potential beneficial effect of cell therapy, achieved by transplanting astrocytes or their precursors. Afterwards, we introduce the different strategies proposed to modulate astrocyte functions in neurodegeneration, ranging from lifestyle changes to environmental cues. Finally, we discuss the challenges and the recent advancements to develop astrocyte-specific delivery systems.

Decoding location-specific and location-invariant stages of numerosity processing in subitizing.

Extracting the number of objects in perceived scenes is a fundamental cognitive ability. Number processing is proposed to rely on two consecutive stages: an early object location map that captures individuated objects in a location-specific way and a subsequent location-invariant representation that captures numerosity at an abstract level. However, it is unclear whether this framework applies to small numerosities that can be individuated at once ("subitized"). Here, we reanalyzed data from two electroencephalography (EEG) experiments using multivariate pattern decoding to identify location-specific and location-invariant stages of numerosity processing in the subitizing range. In these experiments, one to three targets were presented in the left or right hemifield, which allowed for decoding target numerosity within each hemifield separately (location specific) or across hemifields (location invariant). Experiment 1 indicated the presence of a location-specific stage (180-200 ms after stimulus), followed by a location-invariant stage (300 ms after stimulus). A time-by-channel searchlight analysis revealed that the early location-specific stage is most evident at occipital channels, whereas the late location-invariant stage is most evident at parietal channels. Experiment 2 showed that both location-specific and location-invariant components are engaged only during tasks that explicitly require numerosity processing, ruling out automatic, and passive recording of numerosity. These results suggest that numerosity coding in subitizing is strongly grounded on an attention-based, location-specific stage. This stage overlaps with the subsequent activation of a location-invariant stage, where a full representation of numerosity is finalized. Taken together, our findings provide clear evidence for a temporal and spatial segregation of location-specific and location-invariant numerosity coding of small object numerosities.

Inter- and Intra-Hemispheric Age-Related Remodeling in Visuo-Spatial Working Memory.

Electroencephalography (EEG) studies investigating visuo-spatial working memory (vWM) in aging typically adopt an event-related potential (ERP) analysis approach that has shed light on the age-related changes during item retention and retrieval. However, this approach does not fully enable a detailed description of the time course of the neural dynamics related to aging. The most frequent age-related changes in brain activity have been described by two influential models of neurocognitive aging, the Hemispheric Asymmetry Reduction in Older Adults (HAROLD) and the Posterior-Anterior Shift in Aging (PASA). These models posit that older adults tend to recruit additional brain areas (bilateral as predicted by HAROLD and anterior as predicted by PASA) when performing several cognitive tasks. We tested younger (N = 36) and older adults (N = 35) in a typical vWM task (delayed match-to-sample) where participants have to retain items and then compare them to a sample. Through a data-driven whole scalp EEG analysis we aimed at characterizing the temporal dynamics of the age-related activations predicted by the two models, both across and within different stages of stimulus processing. Behaviorally, younger outperformed older adults. The EEG analysis showed that older adults engaged supplementary bilateral posterior and frontal sites when processing different levels of memory load, in line with both HAROLD and PASA-like activations. Interestingly, these age-related supplementary activations dynamically developed over time. Indeed, they varied across different stages of stimulus processing, with HAROLD-like modulations being mainly present during item retention, and PASA-like activity during both retention and retrieval. Overall, the present results suggest that age-related neural changes are not a phenomenon indiscriminately present throughout all levels of cognitive processing.

Learning by task repetition enhances object individuation and memorization in the elderly.

A decline in visuospatial Working Memory (vWM) is a hallmark of cognitive aging across various tasks, and facing this decline has become the target of several studies. In the current study we tested whether older adults can benefit from task repetition in order to improve their performance in a vWM task. While learning by task repetition has been shown to improve vWM performance in young adulthood, little is known on whether a similar enhancement can be achieved also by the aging population. By combining different behavioral and electrophysiological measures, we investigated whether practicing a specific task (delayed match-to-sample judgement) over four consecutive sessions could improve vWM in healthy aging, and which are the neurophysiological and cognitive mechanisms modulated by learning. Behavioral data revealed that task repetition boosted performance in older participants, both in terms of sensitivity to change (as revealed by d' measures) as well as capacity estimate (as measured by k values). At the electrophysiological level, results indicated that only after task repetition both target individuation (as evidenced by the N2pc) and vWM maintenance (as reflected by the CDA) were modulated by target numerosity. Our results suggest that repetition learning is effective in enhancing vWM in aging and acts through modifications at different stages of stimulus processing.

Sleeping Beauty-engineered CAR T cells achieve antileukemic activity without severe toxicities.

BACKGROUNDChimeric antigen receptor (CAR) T cell immunotherapy has resulted in complete remission (CR) and durable response in highly refractory patients. However, logistical complexity and high costs of manufacturing autologous viral products limit CAR T cell availability.METHODSWe report the early results of a phase I/II trial in B cell acute lymphoblastic leukemia (B-ALL) patients relapsed after allogeneic hematopoietic stem cell transplantation (HSCT) using donor-derived CD19 CAR T cells generated with the Sleeping Beauty (SB) transposon and differentiated into cytokine-induced killer (CIK) cells.RESULTSThe cellular product was produced successfully for all patients from the donor peripheral blood (PB) and consisted mostly of CD3+ lymphocytes with 43% CAR expression. Four pediatric and 9 adult patients were infused with a single dose of CAR T cells. Toxicities reported were 2 grade I and 1 grade II cytokine-release syndrome (CRS) cases at the highest dose in the absence of graft-versus-host disease (GVHD), neurotoxicity, or dose-limiting toxicities. Six out of 7 patients receiving the highest doses achieved CR and CR with incomplete blood count recovery (CRi) at day 28. Five out of 6 patients in CR were also minimal residual disease negative (MRD-). Robust expansion was achieved in the majority of the patients. CAR T cells were measurable by transgene copy PCR up to 10 months. Integration site analysis showed a positive safety profile and highly polyclonal repertoire in vitro and at early time points after infusion.CONCLUSIONSB-engineered CAR T cells expand and persist in pediatric and adult B-ALL patients relapsed after HSCT. Antileukemic activity was achieved without severe toxicities.TRIAL REGISTRATIONClinicalTrials.gov NCT03389035.FUNDINGThis study was supported by grants from the Fondazione AIRC per la Ricerca sul Cancro (AIRC); Cancer Research UK (CRUK); the Fundación Científica de la Asociación Española Contra el Cáncer (FC AECC); Ministero Della Salute; Fondazione Regionale per la Ricerca Biomedica (FRRB).