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FMS-like tyrosine kinase 3 (FLT3) is a transmembrane protein expressed on normal hematopoietic stem and progenitor cells (HSC) and retained on malignant blasts in acute myeloid leukemia (AML). We engineered CD8+ and CD4+ T-cells expressing a FLT3-specific chimeric antigen receptor (CAR) and demonstrate they confer potent reactivity against AML cell lines and primary AML blasts that express either wild-type FLT3 or FLT3 with internal tandem duplication (FLT3-ITD). We also show that treatment with the FLT3-inhibitor crenolanib leads to increased surface expression of FLT3 specifically on FLT3-ITD+ AML cells and consecutively, enhanced recognition by FLT3-CAR T-cells in vitro and in vivo. As anticipated, we found that FLT3-CAR T-cells recognize normal HSCs in vitro and in vivo, and disrupt normal hematopoiesis in colony-formation assays, suggesting that adoptive therapy with FLT3-CAR T-cells will require subsequent CAR T-cell depletion and allogeneic HSC transplantation to reconstitute the hematopoietic system. Collectively, our data establish FLT3 as a novel CAR target in AML with particular relevance in high-risk FLT3-ITD+ AML. Further, our data provide the first proof-of-concept that CAR T-cell immunotherapy and small molecule inhibition can be used synergistically, as exemplified by our data showing superior antileukemia efficacy of FLT3-CAR T-cells in combination with crenolanib.

Background The number and size of multi-omics datasets with paired measurements of the host and microbiome is rapidly increasing with the advance of sequencing technologies. As it becomes routine to generate these datasets, computational methods to aid in their interpretation become increasingly important. Here, we present a framework for integration of microbiome multi-omics data: Latent Interacting Variable Effects (LIVE) modeling. LIVE integrates multi-omics data using single-omic latent variables (LV) organized in a structured meta-model to determine the combinations of features most predictive of a phenotype or condition. Results We developed a supervised version of LIVE leveraging sparse Partial Least Squares Discriminant Analysis (sPLS-DA) LVs, and an unsupervised version leveraging sparse Principal Component Analysis (sPCA) principal components which both can incorporate covariate awarness. LIVE performance was tested on publicly available metagenomic and metabolomics data set from Crohn’s Disease (CD) and Ulcerative Colitis (UC) status patients in the PRISM and LLDeep cohorts, and benchmarked against existing gut microbiome multi-omics approaches and vaginal microbiome datasests, achieving consistent and comparable performances. In addition to these benchmarking efforts, we present a detailed analysis and interpretation of both versions of LIVE using the PRISM and LLDeep cohorts. LIVE reduced the number of feature interactions from the original datasets for CD and UC from millions to less than 20,000 while conditioning the disease-predictive power of gut microbes, metabolites, enzymes, on clinical variables. Conclusions LIVE makes a distinct, complementary contribution to current methods to integrate microbiome data and offers key advantages to existing approaches in the interpretable integration of multi-omics data with clinical variables to predict to disease outcomes and identify microbiome mechanisms of disease.

Immunotherapy with T cells genetically modified with chimeric antigen receptors (CARs) has shown significant clinical efficacy in patients with relapsed/refractory B-cell lymphoma. Nevertheless, more than 50% of treated patients do not benefit from such therapy due to either absence of response or further relapse. Elucidation of clinical and biological features that would predict clinical response to CART19 therapy is of paramount importance and eventually may allow for selection of those patients with greater chances of response. In the last 5 years, significant clinical experience has been obtained in the treatment of diffuse large B-cell lymphoma (DLBCL) patients with CAR19 T cells, and major advances have been made on the understanding of CART19 efficacy mechanisms. In this review, we discuss clinical and tumor features associated with response to CART19 in DLBCL patients as well as the impact of biological features of the infusion CART19 product on the clinical response. Prognosis of DLBCL patients that fail CART19 is poor and therapeutic approaches with new drugs are also discussed.

Children with learning disorders (LD) perform below average in tests of academic abilities and intelligence. These children also have a significantly abnormal resting-state electroencephalogram (EEG) compared to children with typical development (TD), i.e. , an excess of slow brain oscillations such as delta and theta that may be markers of inefficient cognitive processing. We aimed to explore the relationship between the performance in an intelligence test and the resting-state EEG power spectrum of children with LD. Ninety-one children with LD and 45 control children with TD were evaluated with the Wechsler Intelligence Scale for Children 4th Edition (WISC-IV) test of intelligence and a 19-channel EEG during an eyes-closed resting-state condition. The EEG dimensionality was reduced with a principal component analysis that yielded several components representing EEG bands with functional meaning. The first seven EEG components and the intelligence values were analyzed with multiple linear regression and a between-group discriminant analysis. The EEG power spectrum was significantly related to children’s intelligence, predicting 13.1% of the IQ variance. Generalized delta and theta power were inversely related to IQ, whereas frontoparietal gamma activity was directly related. The intelligence test and the resting state EEG had a combined 82.4% success rate to discriminate between children with TD and those with LDs.

Tisagenlecleucel (tisa‐cel) is a second‐generation autologous CD19‐targeted chimeric antigen receptor (CAR) T‐cell therapy approved for relapsed/refractory (R/R) large B‐cell lymphoma (LBCL). The approval was based on the results of phase II JULIET trial, with a best overall response rate (ORR) and complete response (CR) rate in infused patients of 52% and 40%, respectively. We report outcomes with tisa‐cel in the standard‐of‐care (SOC) setting for R/R LBCL. Data from all patients with R/R LBCL who underwent leukapheresis from December 2018 until June 2020 with the intent to receive SOC tisa‐cel were retrospectively collected at 10 Spanish institutions. Toxicities were graded according to ASTCT criteria and responses were assessed as per Lugano 2014 classification. Of 91 patients who underwent leukapheresis, 75 (82%) received tisa‐cel therapy. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 5% and 1%, respectively; non‐relapse mortality was 4%. Among the infused patients, best ORR and CR were 60% and 32%, respectively, with a median duration of response of 8.9 months. With a median follow‐up of 14.1 months from CAR T‐cell infusion, median progression‐free survival and overall survival were 3 months and 10.7 months, respectively. At 12 months, patients in CR at first disease evaluation had a PFS of 87% and OS of 93%. Patients with an elevated lactate dehydrogenase showed a shorter PFS and OS on multivariate analysis. Treatment with tisa‐cel for patients with relapsed/refractory LBCL in a European SOC setting showed a manageable safety profile and durable complete responses. This article provides real‐world European data on the results of relapsed/refractory large B‐cell lymphoma patients treated with tisagenlecleucel.

The rising global cancer burden underscores the urgent need for innovative and effective therapies. Molecular and cellular immunology advances have revolutionized cancer immunotherapy, transforming laboratory discoveries into clinical breakthroughs. The Second Bone Marrow Transplant and Cellular Therapy Congress, held in Abu Dhabi, United Arab Emirates (UAE), on October 26 th - 27 th , 2024, and sponsored by the Abu Dhabi Stem Cells Center (ADSCC), convened global experts to discuss cutting-edge developments in adoptive cell transfer (ACT); chimeric antigen receptor T-cell (CAR-T) therapy, tumor-infiltrating lymphocyte (TIL) engineering and T-cell receptor (TCR) innovations. Discussions covered key challenges such as tumor microenvironment (TME) resistance, antigen escape, manufacturing complexity, cost-effectiveness, and accessibility. Experts emphasized the crucial role of biomarker identification in optimizing patient selection and improving treatment efficacy. Additionally, emerging strategies were highlighted to enhance the durability and specificity of cellular therapies, including next-generation CAR-T designs, combination approaches, and novel gene-editing technologies. With over 2,300 participants from academia, research, and healthcare, the event fostered international collaborations and knowledge exchange. The ADSCC continues to play a pivotal role in integrating advanced cellular therapies into healthcare systems, contributing to the expansion of precision oncology in the UAE and beyond. This review analyzes the latest advances in immunotherapy, highlighting their clinical impact, challenges, and future directions in the evolving landscape of cancer treatment, as debated during the congress.

Children with learning disorders (LD children) often have heterogeneous cognitive impairments that affect their ability to learn and use basic academic skills. A proposed cause for this variability has been working memory (WM) capacity. Altered patterns of event-related potentials (ERPs) in these children have also been found in the N400 component associated with semantic priming. However, regarding the semantic priming effect in LD children, no distinction has been made for children with varying WM abilities. This study aims to explore the relationship of WM with the brain’s electrophysiological response that underlies semantic priming in LD children that performed a lexical decision task. A total of 40 children (8-10 years old) participated: 28 children with LD and 12 age-matched controls. The ERPs were recorded for each group and analyzed with permutation-based t-tests. The N400 effect was observed only in the control group, and both groups showed a late positive complex (LPC). Permutation-based regression analyses were performed for the results from the LD group using the WISC-IV indices (e.g., Verbal Comprehension and WM) as independent predictors of the ERPs. The Verbal Comprehension Index, but not the WM index, was a significant predictor of the N400 and LPC effects in LD children.

Electroencephalograms (EEGs) of children with reading disorders (RDs) are characterized by a higher theta and a lower alpha than those of typically developing children. Neurofeedback (NFB) may be helpful for treating learning disorders by reinforcing a reduction in the theta/alpha ratio. Several studies have suggested that NFB may lead to EEG power normalization and cognitive improvements. To further explore brain changes in isolated areas, the aim of this study was to explore the effects of an NFB protocol on functional connectivity (coherence) among children with RDs. Twenty children with an RD and an abnormally high theta/alpha ratio underwent 30 NFB sessions, and five children with the same characteristics received a sham NFB treatment. On average, the children in the NFB group showed an increase in reading accuracy and comprehension scores; their coherence diminished in the delta, theta, and beta bands and increased in the alpha band, primarily the theta intrahemispheric coherences of the left hemisphere, which is closely associated with reading. In contrast, children who received the sham NFB treatment did not show reading changes and had few changes in their coherence patterns. These preliminary results suggest that NFB can positively impact reading-related functions in the brain networks of children with RDs.

Home hospitalization represents an alternative to traditional hospitalization, providing comparable clinical safety for hematological patients. At-home therapies can range from the delivery of intravenous antibiotics to more complex scenarios, such as the care during the early period after hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy. Early discharge from conventional hospitalization is feasible and helps reduce hospital resources and waiting lists. The coordinated efforts of multidisciplinary teams, including hematologists, nurses, and pharmacists, ensure patient safety and continuity of care. The traditional model of home hospitalization relies on home visits and telephone consultations with physicians and nurses. However, the use of eHealth technologies, such as MY-Medula, can enhance communication and monitoring, and thereby improve patient outcomes with no additional costs. The active involvement of a clinical pharmacist in home hospitalization programs is essential, not only for the proper logistical management of the medication but also to ensure its appropriateness, optimize treatment, address queries from the team and patients, and promote adherence. In conclusion, the implementation of hematopoietic stem cell transplantation and chimeric antigen receptor T-cell therapy home hospitalization programs that use both an eHealth tool and a multidisciplinary care model can optimize patient care and improve quality of life without increasing healthcare costs.

Background Invariant natural killer T (iNKT) cells are a small population of lymphocytes with unique specificity for glycolipid antigens presented by non-polymorphic CD1d receptor on dendritic cells (DCs). iNKT cells play a central role in tumor immunology since they are implicated in the coordination of innate and adaptive immune responses. These cells can be activated with the prototypic lipid α-galactosylceramide (α-GalCer), stimulating interferon gamma (IFN-γ) production and cytokine secretion, which contribute to the enhancement of T cell activation. Methods We evaluated the antitumor effect of a combination of dendritic cells (DCs) and tumor cells with the iNKT cell agonist α-GalCer in a therapeutic model of B cell lymphoma. iNKT, NK and T cell phenotype was determined by flow cytometry. Serum cytokines were analyzed by Luminex technology. Significant differences between survival curves were assessed by the log-rank test. For all other data, Mann–Whitney test was used to analyze the differences between groups. Results This vaccine induced a potent (100% survival), long-lasting and tumor-specific antitumor immune response, that was associated with an increase of both Th1 cytokines and IFN-γ secreting iNKT cells (4.59 ± 0.41% vs. 0.92 ± 0.12% in control group; p = 0.01) and T cells (CD4 IFN-γ + : 3.75 ± 0.59% vs. 0.66 ± 0.18% p = 0.02; CD8 IFN-γ + : 10.61 ± 0.84% vs. 0.47 ± 0.03% p = 0.002). Importantly, natural killer (NK) cells played a critical role in the antitumor effect observed after vaccination. Conclusions This study provides clinically relevant data for the development of iNKT-cell based immunotherapy treatments for patients with B cell malignancies.