Blood最新文献

VCAR33, a donor-derived CD33-directed chimeric antigen receptor (CAR) T cell product, was developed to decrease relapse of high-risk acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (alloHCT). We describe pre-clinical characterization of the VCAR33 construct, which was optimized for long-term anti-tumor surveillance based on killing and persistence assays. Prior to its use in post-alloHCT maintenance, we evaluated safety and efficacy of VCAR33 in a phase 1/2 clinical study for adults with relapsed or measurable residual disease (MRD)-positive CD33+ AML/MDS after alloHCT. Fifteen patients received VCAR33 across 2 arms stratified by disease burden: 7 patients in Arm A (bone marrow blasts ≥ 5%) at dose level 1 (DL1; 1 x 106 CAR+ T cells/kg) and 8 patients in Arm B (bone marrow blasts < 5%) at DL1 (n=5) and DL2 (3 x 106 CAR+ T cells/kg; n=3). The study ended for non-safety reasons before escalation to DL3 (1 x 107 CAR+ T cells/kg) and maximum tolerated dose was not determined. The most common treatment-related adverse event was cytokine release syndrome (93.3%; all < grade 3). Four patients (26.7%) experienced immune cell-associated neurotoxicity syndrome (1 ≥ grade 3) and 1 patient (6.7%) had grade III acute graft-versus-host disease within 28 days of VCAR33 infusion. Fourteen patients (93.3%) had transient VCAR33 expansion. Overall response rate was 20%: 2 patients had complete remission with incomplete count recovery in Arm A and 1 Arm B patient achieved MRD clearance. This allogeneic CAR T product demonstrated acceptable safety and preliminary anti-leukemic activity. ClinicalTrials.gov: NCT05984199.

Immune thrombocytopenia (ITP) is associated with a variable and unpredictable clinical course in children, including a spectrum of bleeding and systemic symptoms in the months following diagnosis. Although many children will have spontaneous resolution of disease prior to 1 year, up to 30% will go on to develop chronic disease. Known predictors for developing chronic ITP are limited, making clinical management and guidance during this early course of disease very challenging. Additionally, the pathophysiology of immune dysregulation in ITP is complex, with multiple variables likely contributing to the development of chronic disease. We aimed to create a statistical model to predict development of chronic ITP. Utilizing a retrospective training cohort of 611 children with ITP from two institutions and two validation cohorts comprised of 161 children, we developed and validated a multivariable logistic regression model and found that age, sex, IgG, IgA, IgM, presenting platelet count, presenting lymphocyte count, known secondary cause at diagnosis, and DAT positivity were useful in predicting chronic ITP. The external validations demonstrated consistent discriminative performance and clinical utility. The model is available for use at https://opal.shinyapps.io/citp-rm/. A chronicity prediction tool to use at the time of ITP diagnosis will better equip hematologists to counsel patients and families and engage in appropriate treatment strategies for individual patients earlier in their course.

We found that PSMD1, a key subunit of the 19S proteasome regulatory particle, was overexpressed and correlated with poor prognosis in multiple myeloma (MM). Genetic depletion of PSMD1 decreased cancer cell viability, induced polyubiquitinated protein accumulation, and promoted apoptosis. Proteomic analysis revealed the activation of immune-related pathways, suggesting the potential for immune modulation. Targeting PSMD1 with siRNA, delivered via lipid nanoparticles (LNPs), reduced tumor growth in MM cell lines and primary patient samples while sparing normal cells. It also overcame proteasome inhibitor resistance and the protective effects of the bone marrow milieu. In MM xenograft mouse models, PSMD1 siRNA LNPs significantly reduced tumor growth and prolonged survival. In addition, PSMD1 depletion had similar effects on other types of cancer cell lines. These findings position PSMD1 as a critical target in cancer therapy, with broad implications for overcoming drug resistance, improving therapeutic outcomes, and potentially impacting immune responses across various cancers. These findings provide a foundation for the clinical development of PSMD1-targeted therapies in myeloma and other malignancies.

Abstract: Self-renewal and differentiation are at the basis of hematopoiesis. Although it is known that tight regulation of translation is vital for hematopoietic stem cells' (HSC) biology, the mechanisms underlying translation regulation across the hematopoietic system remain obscure. Here, we reveal a novel mechanism of translation regulation in the hematopoietic hierarchy, which is mediated by rRNA methylation dynamics. Using ultralow-input ribosome profiling, we characterized cell-type-specific translation capacity during erythroid differentiation. We found that translation efficiency (TE) changes progressively with differentiation and can distinguish between discrete cell populations, as well as define differentiation trajectories. To reveal the underlying mechanism, we performed comprehensive mapping of the most abundant rRNA modification, 2'-O-methyl (2'OMe). We found that, such as TE, 2'OMe dynamics followed a distinct trajectory during erythroid differentiation. Genetic perturbation of individual 2'OMe sites demonstrated their distinct roles in modulating proliferation and differentiation. By combining CRISPR screening, molecular, and functional analyses, we identified a specific methylation site, 28S-Gm4588, which is progressively lost during differentiation, as a key regulator of HSC self-renewal. We showed that low methylation at this site led to translational skewing, mediated mainly by codon frequency, which promoted differentiation. Functionally, HSC with diminished 28S-Gm4588 methylation exhibited impaired self-renewal capacity ex vivo, and loss of fitness in vivo in bone marrow transplants. Extending our findings beyond the hematopoietic system, we also found distinct dynamics of 2'OMe profiles during differentiation of non-HSC. Our findings reveal rRNA methylation dynamics as a general mechanism for cell-type-specific translation, required for cell function and differentiation.