Blood advances最新文献

Compared to total body irradiation or chemotherapy, antibody-drug conjugates (ADCs) offer a more targeted and potentially less toxic method for transplant conditioning. CD45-ADC targets a pan-leukocyte antigen expressed on HSPCs and immune cells, offering a promising strategy for gene therapy or allogeneic transplantation. We evaluated reconstitution, clonal dynamics, immune tolerance, and toxicity following conditioning with a DGN549-C-conjugated CD45-ADC followed by autologous transplantation in rhesus macaques. Two doses (0.2 and 0.3 mg/kg) were tested, with HSPC infusion 10 days post-conditioning. All animals received barcoded, CopGFP-expressing lentivirally transduced HSPCs. Both doses resulted in profound depletion of HSPCs and expected cytopenias, with incomplete lymphocyte depletion. With 0.2 mg/kg CD45-ADC conditioning, two animals showed robust multilineage engraftment with gene-modified cells and high clonal diversity, comparable to TBI. However, CopGFP+ cell levels and clonal diversity declined at 4-8 months, accompanied by development of anti-CopGFP antibodies, suggesting immune rejection. Incomplete T-cell depletion may have contributed. Notably, this rejection was slower and less complete than following busulfan conditioning, suggesting partial immune tolerance. Dexamethasone treatment in one animal reversed rejection and stabilized CopGFP+ levels for over 2 years. At 0.3mg/kg CD45-ADC, two animals developed severe respiratory distress 4-6 days post-transplantation, requiring humane euthanasia, accompanied by elevated inflammatory cytokines. This severe syndrome was not seen in 9 additional animals conditioned with CD45-ADC. These findings highlight the importance of pre-clinical evaluation of experimental therapeutics. Combining lower-dose CD45-ADC with immune suppression may enable durable engraftment in settings of alloantigen or neoantigen expression.

Abstract: Multiple myeloma (MM) is a plasma cell malignancy characterized by bone pain and end-organ failure. A major challenge in treating MM is therapeutic resistance. CD38-targeted immunotherapies, such as daratumumab, have significantly improved outcomes; however, variable responses, resistance, and relapse remain vital challenges. We hypothesized that loss of CD38 drives a more aggressive phenotype and resistance to therapy. To test this, we developed a CD38 knockout (KO) clone of a human MM cell line and evaluated it in immunodeficient mice. Mice with CD38 KO tumors exhibited an increased tumor burden and reduced survival compared with those with CD38 wild-type (WT) tumors. Multimodal imaging and histologic analyses revealed increased osteolytic lesions caused by CD38 KO tumors, while [18F]-fluorodeoxyglucose positron emission tomography demonstrated elevated metabolic activity and tracer uptake. Mice with CD38 KO tumors also developed bilateral renal metastases, whereas none were observed in WT tumors. Blood analysis showed elevated markers of disease progression and renal dysfunction, and cytokine profiling identified increased proinflammatory cytokines within the bone microenvironment. RNA sequencing identified marked transcriptional changes, with enrichment of pathways involving cell adhesion, cytokine signaling, and migration. Daratumumab-resistant MM.1S cells mirrored CD38 KO cells with reduced cell cycle progression and dexamethasone sensitivity, underscoring the microenvironment's role in driving aggressiveness, and implicating CD38 loss as a possible mediator of cross-resistance. Overall, these findings demonstrate that CD38 loss drives an aggressive MM phenotype characterized by bone degradation, renal metastasis, and reduced survival, highlighting the need to develop strategies to target CD38-deficient clones and identifying RNA signatures as potential regulators of this phenotype.

Abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a malignant proliferation of T-cell progenitors originating in the thymus. T-ALL is a heterogenous disease involving the dysregulation of various oncogenes/tumor-suppressor (TS) genes. Loss of the TS gene phosphatase and TENsin homolog (PTEN) is a recurrent alteration, which is often associated with a mature T-ALL subgroup expressing a T-cell receptor. Herein, we used a single-cell RNA-sequencing approach to investigate the impact of the absence of PTEN on pathological development of mouse thymocytes. First, our differential gene expression analysis of tumor cells vs physiologic cells uncovers an ectopic expression, in leukemic cells, of the gene encoding Bex1. Then, to determine the relevance of our observation in humans, we queried a public RNA-sequencing database from the TARGET-TCGA (Therapeutically Applicable Research to Generate Effective Treatments-The Cancer Genome Atlas) project. We show that BEX1, BEX2, and BEX5 genes are ectopically expressed in T-ALL samples and we further found that ectopic BEX expression is mainly restricted to the T-ALL subgroup overexpressing TAL1 oncogene. Proximity ligation assays demonstrated the nuclear colocalization of brain-expressed X-linked 1/2 (BEX1/2) proteins with T-cell acute lymphocytic leukemia protein 1 (TAL1) in T-ALL cells. To investigate their functional role, we generated Jurkat cells with a triple knockout of BEX1, BEX2, and BEX5 using CRISPR-CRISPR-associated protein 9. This genetic inactivation led to reduced cell proliferation, a loss of histone H3 lysine 4 monomethylation (H3K4me1) marks notably at genomic regions enriched for E-box motifs, and dysregulation of several TAL1 target genes. Collectively, our findings suggest that BEX1 and BEX2 may contribute to human T-ALL oncogenesis by acting as cofactors within the TAL1 complex.

Abstract: Patients with relapsed/refractory multiple myeloma (RRMM) frequently develop drug resistance, leading to poor survival outcomes. Zevorcabtagene autoleucel (zevor-cel or CT053) is a fully human B-cell maturation antigen, targeting chimeric antigen receptor (CAR) T-cell therapy for patients with RRMM. The phase 1 part of LUMMICAR study 1 was a single-arm, open-label, multi-center study conducted in China, enrolling patients with RRMM who received ≥3 prior regimens. Safety, tolerability, efficacy, and pharmacokinetics were evaluated. Fourteen patients (50% male) received single infusion of zevor-cel (100 × 106 [n = 3] and 150 × 106 CAR T cells [n = 11]). As of 22 February 2025, with the median follow-up duration of 53.3 months (range, 14.8-63.5), 13 (92.9%) patients experienced grade 1 or 2 cytokine release syndrome. No immune effector cell-associated neurotoxicity syndrome, delayed neurotoxicities, second primary malignancy, or other delayed adverse events were observed. There were 3 deaths, and none were zevor-cel-related. The objective response rate was 100% (95% confidence interval [CI], 76.8-100.0) and 11 (78.6%) patients achieved complete response or better, 13 (92.9%) with very good partial response or better response and 1 (7.1%) with partial response. The median duration of response was 24.94 months (95% CI, 14.03-45.86). The proportion of patients with a response lasting ≥36 months and ≥48 months were 41.7% and 15.6%, respectively. At 24, 36, 48, and 60 months after infusion, overall survival rates were 100%, 92.3%, 84.6%, and 76.9%, respectively. This 53.3-month median follow-up data of zevor-cel reaffirms the initial results with a manageable safety profile and compelling efficacy in RRMM. This trial was registered at www.clinicaltrials.gov (NCT03975907).

Abstract: Large B-cell lymphoma (LBCL) patients failing anti-CD19 chimeric antigen receptor (CAR) T-cell therapy exhibit poor prognosis. Most progressions/relapses occur within 3 months from infusion whereas only a few events occur thereafter (late failure, [LF]). We analyze features, treatments, and outcomes of patients with LF from DESCAR-T, a nationwide registry collecting real-life data for patients treated with approved CAR T-cell therapy in France. Between July 2018 and March 2024, 298 (39.9%) LBCL LF patients (median age, 62 years [range, 18-79]; male, 61.7%) were collected from DESCAR-T. Most patients had diffuse LBCL (n = 205 [68.8%]), advanced stage disease (84.6%), and age-adjusted International Prognostic Index of 2 to 3 (59.3%) at CAR T-cell eligibility. After failure, 76.5% of patients received a systemic therapy and overall response rate was 22.6% (complete response, 18%). At a median follow-up since first LF event of 13.8 months (95% confidence interval [CI], 12.1-15.4), the median overall survival and progression-free survival 2 (PFS-2) were 4.4 (95% CI, 3.8-5.8) and 13.2 (95% CI, 9.6-18) months, respectively. Compared with chemotherapy (hazard ratio [HR], 0.350; 95% CI, 0.193-0.633) and with pooled other treatment groups (HR, 0.483; 95% CI, 0.290-0.805), salvage treatment with bispecific antibodies (bsAb) after CAR T-cell failure showed better PFS-2. Radiotherapy obtained prolonged responses in some patients with 12-month PFS-2 of 41.5% (95% CI, 22.5-59.5). This work is, to our knowledge, the first study describing LBCL patients with LF after CAR T-cells. bsAb seem to be more effective compared with other strategies in the LF setting and this should be considered in the design of new clinical trials.

Abstract: High-grade B-cell lymphoma with "double-hit" MYC and BCL2 rearrangements (HGBCL-DH-BCL2) is associated with poor outcomes following standard chemoimmunotherapy, prompting dose-intensive regimen use. However, the benefit of intensification is unclear due to rarity precluding randomized trials, and selection bias in retrospective comparisons. In 2015, BC Cancer introduced a provincial guideline recommending dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for fit patients aged ≤75 years with HGBCL-DH-BCL2 identified by routine cytogenetic testing. To assess this guideline's impact, we compared the outcomes of patients with de novo HGBCL-DH-BCL2 tumors of diffuse large B-cell lymphoma (DLBCL) morphology across 2 eras. The DA-EPOCH-R era (2015-2020) included patients diagnosed after guideline implementation. The historic era (2005-2010) included patients identified from a historic province-wide cohort of patients with DLBCL morphology tumors that underwent universal cytogenetic testing in a research setting, predominantly treated with standard chemoimmunotherapy. Two-year overall survival (OS) was significantly improved in the DA-EPOCH-R vs historic era (75% vs 47%, P = .008) in HGBCL-DH-BCL2, whereas OS remained unchanged in DLBCL, not otherwise specified (78% vs 76%, P = .17). Within HGBCL-DH-BCL2, tumors harboring immunoglobulin MYC partner loci (43%) and those expressing the dark-zone signature (77%) were associated with the most substantial survival improvements. In a contemporary cohort of HGBCL-DH-BCL2 histologically transformed from follicular lymphoma (FL) in the DA-EPOCH-R era, outcomes of patients who were chemoimmunotherapy-naïve were comparable to those with de novo disease, whereas patients treated with chemoimmunotherapy for FL prior to transformation had poor outcomes. These data support using DA-EPOCH-R in select patients with HGBCL-DH-BCL2 of DLBCL morphology.

Systemic amyloidosis is a rare, multisystem disorder that is often challenging to diagnose due to vague and non-specific symptoms that frequently overlap with other disorders. By the time patients are diagnosed, irreversible organ impairment from amyloid deposition has occurred, contributing to substantial morbidity and mortality. While developing the American Society of Hematology (ASH) guidelines on systemic amyloidosis, we identified a critical knowledge gap in the recognition of the clinical presentation of its most common subtypes. Therefore, we conducted a scoping review of 117 studies following PRISMA-ScR guidelines to identify clinical "red flags" for light chain (AL) and transthyretin (ATTRwt, ATTRv) amyloidosis. Studies were identified from the comprehensive systematic review through the ASH amyloidosis diagnosis guideline panel, data mining, and grey literature review. Data were extracted and synthesized by systems to characterize the earliest and most frequently overlooked clinical red flags for the different types of amyloidosis. Shortness of breath and fatigue, the earliest symptoms of AL amyloidosis, contrast with the carpal tunnel syndrome occurring years before ATTRwt cardiac amyloidosis is diagnosed. Weight loss, unexplained abdominal pain, and early satiety were overlooked red flags for AL amyloidosis, compared to the preceding arrhythmias often missed in evaluation for ATTRwt amyloidosis. Sensory loss was the predominant neuropathic presentation for AL amyloidosis compared to the painful length-dependent neuropathy of ATTRv amyloidosis. Awareness of the early symptoms and distinct patterns across subtypes can enhance cross-specialty awareness and support earlier diagnosis and intervention of AL and ATTR amyloidosis.

Abstract: Early detection of ultrahigh-risk diffuse large B-cell lymphoma (DLBCL) is an unmet medical need to aid patient stratification for alternative treatment approaches. Metabolomics applied to biofluids of patients with cancer has emerged as a novel omics that could provide important information to better stratify these patients. In this work, the authors performed a retrospective study by nuclear magnetic resonance (NMR)-based metabolomics using plasma samples at diagnosis from 154 randomized patients with DLBCL treated by R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) (from the phase 3 REMARC [Reduced-intensity Maintenance therapy with Rituximab After R-CHOP in elderly patients with DLBCL] trial). Remarkably, a combination of 3 circulating metabolites was linked to lipid metabolism (named the "NMR score") that significantly affected overall survival (OS) (P< .0001) and progression-free survival (PFS) (P = .0003). The optimal cutoff for each metabolite was determined using X-Tile and confirmed by a training validation method. Combining 2-amino-butyrate, 3-hydroxy-butyrate, and LDL-1 lipoprotein yielded 3 risk groups with low- (0-1), intermediate- (2-3), and high-risk (4-5) patients. Germinal center B-cell (GCB)/non-GCB profile along with Bcl2 and Myc expression did not correlate with NMR score survival. In conclusion, the combination of 3 circulating metabolites linked to lipid metabolism is revealed as a feature that captures heterogeneity among patients with DLBCL. This NMR score seemed promising for DLBCL risk stratification, even among responder patients after R-CHOP treatment. This trial was registered at www.ClinicalTrials.gov as #NCT01122472.