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Chimeric antigen receptors (CAR) are engineered fusion proteins designed to target T cells to antigens expressed on cancer cells. CAR T cells are now an established treatment for patients with relapsed and/or refractory B cell lymphomas, B cell acute lymphoblastic leukaemia and multiple myeloma. At the time of this writing, over a decade of follow-up data are available from the initial patients who received CD19-targeted CAR T cells for B cell malignancies. Data on the outcomes of patients who received B cell maturation antigen (BCMA)-targeted CAR T cells for multiple myeloma are more limited owing to the more recent development of these constructs. In this Review, we summarize long-term follow-up data on efficacy and toxicities from patients treated with CAR T cells targeting CD19 or BCMA. Overall, the data demonstrate that CD19-targeted CAR T cells can induce prolonged remissions in patients with B cell malignancies, often with minimal long-term toxicities, and are probably curative for a subset of patients. By contrast, remissions induced by BCMA-targeted CAR T cells are typically more short-lived but also generally have only limited long-term toxicities. We discuss factors associated with long-term remissions, including the depth of initial response, malignancy characteristics predictive of response, peak circulating CAR levels and the role of lymphodepleting chemotherapy. We also discuss ongoing investigational strategies designed to improve the length of remission following CAR T cell therapy.Chimeric antigen receptor (CAR) T cells have dramatically improved the outcomes of patients with certain relapsed and/or refractory haematological malignancies. Owing to the promising short-term survival outcomes achieved, long-term data on both safety and survival are becoming increasingly relevant. In this Review, the authors describe the available long-term follow-up data from early studies testing the safety and efficacy of receiving CAR T cells targeting CD19 as well as more recent data on BCMA-targeted CAR T cells in patients with relapsed and/or refractory multiple myeloma.

Devimistat is a TCA cycle inhibitor. A previously completed phase I study of devimistat in combination with cytarabine and mitoxantrone in patients with relapsed or refractory AML showed promising response rates. Here we report the results of a single arm phase II study (NCT02484391). The primary outcome of feasibility of maintenance devimistat following induction and consolidation with devimistat in combination with high dose cytarabine and mitoxantrone was not met, as maintenance devimistat was only administered in 2 of 21 responders. The secondary outcomes of response (CR + CRi) and median survival were 44% (21/48) and 5.9 months respectively. There were no unexpected toxicities observed. An unplanned, post-hoc analysis of the phase I and II datasets suggests a trend of a dose response in older but not younger patients. RNA sequencing data from patient samples reveals an age-related decline in mitochondrial gene sets. Devimistat impairs ATP synthesis and we find a correlation between mitochondrial membrane potential and sensitivity to chemotherapy. Devimistat also induces mitochondrial reactive oxygen species and turnover consistent with mitophagy. We find that pharmacological or genetic inhibition of mitochondrial fission or autophagy sensitizes cells to devimistat. These findings suggest that an age related decline in mitochondrial quality and autophagy may be associated with response to devimistat however this needs to be confirmed in larger cohorts with proper trial design. Combining cytarabine and mitoxantrone with the tricarboxylic acid cycle inhibitor devimistat has been reported in a phase I clinical trial with relapsed or refractory acute myeloid leukaemia (AML). Here, the authors report the outcomes of a phase II study, analyse samples from both phases and perform preclinical analyses that show mitochondrial fission or autophagy inhibition sensitizes AML cells to devimistat.

Clinical recommendations for Acute Myeloid Leukemia (AML) classification and risk-stratification remain heavily reliant on cytogenetic findings at diagnosis, which are present in <50% of patients. Using comprehensive molecular profiling data from 3,653 patients we characterize and validate 16 molecular classes describing 100% of AML patients. Each class represents diverse biological AML subgroups, and is associated with distinct clinical presentation, likelihood of response to induction chemotherapy, risk of relapse and death over time. Secondary AML-2, emerges as the second largest class (24%), associates with high-risk disease, poor prognosis irrespective of flow Minimal Residual Disease (MRD) negativity, and derives significant benefit from transplantation. Guided by class membership we derive a 3-tier risk-stratification score that re-stratifies 26% of patients as compared to standard of care. This results in a unified framework for disease classification and risk-stratification in AML that relies on information from cytogenetics and 32 genes. Last, we develop an open-access patient-tailored clinical decision support tool. Classification and risk-stratification for Acute Myeloid Leukemia (AML) at diagnosis are primarily based on cytogenetics and only a few gene mutations. Here, the authors study the genomic landscape of 3653 AML patients and characterize 16 non-overlapping molecular subgroups of clinical relevance for disease classification and risk prognostication.

The gut microbiota has been linked to many cancers, yet its role in acute myeloid leukaemia (AML) progression remains unclear. Here, we show decreased diversity in the gut microbiota of AML patients or murine models. Gut microbiota dysbiosis induced by antibiotic treatment accelerates murine AML progression while faecal microbiota transplantation reverses this process. Butyrate produced by the gut microbiota (especially Faecalibacterium ) significantly decreases in faeces of AML patients, while gavage with butyrate or Faecalibacterium postpones murine AML progression. Furthermore, we find the intestinal barrier is damaged in mice with AML, which accelerates lipopolysaccharide (LPS) leakage into the blood. The increased LPS exacerbates leukaemia progression in vitro and in vivo. Butyrate can repair intestinal barrier damage and inhibit LPS absorption in AML mice. Collectively, we demonstrate that the gut microbiota promotes AML progression in a metabolite-dependent manner and that targeting the gut microbiota might provide a therapeutic option for AML. The role of gut microbiota in acute myeloid leukaemia (AML) remains unclear. Here, the authors show disordered gut microbiota and reduced butyrate cause intestinal barrier damage in AML mice, with increased plasma LPS that accelerates AML progression.

White Blood Cell (WBC) Leukaemia is caused by excessive production of leukocytes in the bone marrow, and image-based detection of malignant WBCs is important for its detection. Convolutional Neural Networks (CNNs) present the current state-of-the-art for this type of image classification, but their computational cost for training and deployment can be high. We here present an improved hybrid approach for efficient classification of WBC Leukemia. We first extract features from WBC images using VGGNet, a powerful CNN architecture, pre-trained on ImageNet. The extracted features are then filtered using a statistically enhanced Salp Swarm Algorithm (SESSA). This bio-inspired optimization algorithm selects the most relevant features and removes highly correlated and noisy features. We applied the proposed approach to two public WBC Leukemia reference datasets and achieve both high accuracy and reduced computational complexity. The SESSA optimization selected only 1 K out of 25 K features extracted with VGGNet, while improving accuracy at the same time. The results are among the best achieved on these datasets and outperform several convolutional network models. We expect that the combination of CNN feature extraction and SESSA feature optimization could be useful for many other image classification tasks.

Chronic lymphocytic leukaemia (CLL), the most frequent type of leukaemia in adults, is a lymphoproliferative disorder that is characterized by the expansion of monoclonal, mature CD5+CD23+ B cells in the peripheral blood, secondary lymphoid tissues and bone marrow. CLL is an incurable disease with a heterogeneous clinical course, for which the treatment decision still relies on conventional parameters (such as clinical stage and lymphocyte doubling time). During the past 5 years, relevant advances have been made in understanding CLL biology. Indeed, substantial progress has been made in the identification of the putative cell of origin of CLL, and comprehensive studies have dissected the genomic, epigenomic and transcriptomic landscape of CLL. Advances in clinical management include improvements in our understanding of the prognostic value of different genetic lesions, particularly those associated with chemoresistance and progression to highly aggressive forms of CLL, and the advent of new therapies targeting crucial biological pathways. In this Review, we discuss new insights into the genetic lesions involved in the pathogenesis of CLL and how these genetic insights influence clinical management and the development of new therapeutic strategies for this disease.

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level.

This study utilized TCGA database to explore the role of m6A modification and immune infiltration in AML. Through unsupervised clustering and WGCNA analysis, 8 hub genes were identified, and a risk model with EHBP1L1 and ZNF385A was established using LASSO regression. A nomogram incorporating hub gene risk score and age showed satisfactory prognostic prediction. External validation of GEO confirmed the model’s effectiveness. TME analysis revealed correlations with monocytes and Treg cells, while immune checkpoints and HLA genes were associated with risk scores. Drug sensitivity analysis suggested potential responses to specific chemotherapy drugs. TIDE analysis indicated reduced ICI treatment benefit in high-risk patients. RT-qPCR validations revealed the significance of prognosis and risk stratification of ZNF385A . The noticeable trend of EHBP1L1 was observed. In addition, the accurate predictive capability of the risk model has been validated by clinical samples. Therefore, the risk model enables a quantitative evaluation of disease severity and progression risk in AML patients, based on their clinical and biological characteristics. This precise prediction not only informs treatment decisions but also guides the selection of chemotherapy regimens, overall improving patient outcomes.

Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of patients experience suboptimal CAR T cell cytotoxicity and persistence that can permit tumor cell escape and disease relapse. Here we show that a prototype pro-lymphoid growth factor is able to enhance CAR T cell efficacy. We demonstrate that a long-acting form of recombinant human interleukin-7 (IL-7) fused with hybrid Fc (rhIL-7-hyFc) promotes proliferation, persistence and cytotoxicity of human CAR T cells in xenogeneic mouse models, and murine CAR T cells in syngeneic mouse models, resulting in long-term tumor-free survival. Thus, rhIL-7-hyFc represents a tunable clinic-ready adjuvant for improving suboptimal CAR T cell activity. Chimeric antigen receptor T cells represent a breakthrough treatment in hematologic malignancies, but insufficient level of cytotoxicity and persistence of T cells might compromise success. Authors show here that a recombinant long acting form of interleukin-7 enhances proliferation, persistence and cytotoxicity of the engineered T cells, resulting in long term disease remission.

The best-known role of UDP-glucuronosyltransferase enzymes (UGTs) in cancer is the metabolic inactivation of drug therapies. By conjugating glucuronic acid to lipophilic drugs, UGTs impair the biological activity and enhance the water solubility of these agents, driving their elimination. Multiple clinical observations support an expanding role for UGTs as modulators of the drug response and in mediating drug resistance in numerous cancer types. However, accumulating evidence also suggests an influence of the UGT pathway on cancer progression. Dysregulation of the expression and activity of UGTs has been associated with the progression of several cancers, arguing for UGTs as possible mediators of oncogenic pathways and/or disease accelerators in a drug-naive context. The consequences of altered UGT activity on tumour biology are incompletely understood. They might be associated with perturbed levels of bioactive endogenous metabolites such as steroids and bioactive lipids that are inactivated by UGTs or through non-enzymatic mechanisms, thereby eliciting oncogenic signalling cascades. This review highlights the evidence supporting dual roles for the UGT pathway, affecting cancer progression and drug resistance. Pharmacogenomic testing of UGT profiles in patients and the development of therapeutic options that impair UGT actions could provide useful prognostic and predictive biomarkers and enhance the efficacy of anti-cancer drugs.