Blood最新文献

{"title":"How I treat type 1 plasminogen deficiency.","authors":"Amy D Shapiro, Charles Nakar","doi":"10.1182/blood.2024026973","DOIUrl":"https://doi.org/10.1182/blood.2024026973","url":null,"abstract":"<p><p>Type 1 plasminogen deficiency (PLGD), an ultra-rare disorder caused by PLG pathogenic variants, results in decreased levels of immunoreactive and functional plasminogen. PLGD can cause fibrin-rich pseudomembranes on mucosa that impair tissue/organ function, impact quality of life, and are potentially life-threatening. Lesion regression/resolution is facilitated by intravenous administration of human plasma-derived Glu-plasminogen (IV PLG concentrate), the first and only FDA-approved specific treatment, licensed in 2021. The diagnosis of PLGD is frequently delayed due to its rarity (1.6 per million) and the variability of the initial medical specialty contact determined by the affected systems. Symptoms are often attributed to more common conditions, like conjunctivitis, recurrent otitis media, reactive airway disease, etc. This manuscript presents clinical vignettes highlighting strategies for PLGD diagnosis and treatment. Initial evaluation includes a detailed history, laboratory assays, and, at times, radiologic or other procedures. Genetic testing can confirm the diagnosis. Consistent, knowledgeable management is required to promptly identify and treat lesions, even in initially asymptomatic individuals. Personalized treatment may include continuous prophylaxis or intermittent treatment with IV PLG concentrate, dependent on disease severity and clinical course. Specialized facilities like Hemophilia Treatment Centers offering multidisciplinary care represent medical homes for this ultra-rare disorder.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blunted CD40-responsive enhancer activation in CREBBP-mutant lymphomas can be restored by enforced CD4 T-cell engagement.","authors":"Haopeng Yang, Wenchao Zhang, Vida Ravanmehr, Guiling Cui, Kevin Bowman, Ruidong Chen, Jared Henderson, Shyanne Ruby Lockman, Estela Rojas, Ashley Lauren Wilson, Sydney Parsons, Ariel Mechaly, Leslie Regad, Ahmed Haouz, Christopher R Flowers, Sattva S Neelapu, Loretta J Nastoupil, Richard Eric Davis, Qing Deng, Fernando Rodrigues Lima, Michael R Green","doi":"10.1182/blood.2024026664","DOIUrl":"https://doi.org/10.1182/blood.2024026664","url":null,"abstract":"<p><p>The CREBBP lysine acetyltransferase (KAT) is frequently mutated in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) and has been studied using gene knock-out (KO) in murine and human cells. However, the majority of CREBBP mutations encode amino acid substitutions within the catalytic KAT domain (CREBBP KAT-PM) that retain an inactive protein and have not been extensively characterized. Using CRISPR gene editing and extensive epigenomic characterization of lymphoma cell-lines, we found that CREBBP KAT-PM lead to unloading of CREBBP from chromatin, loss of enhancer acetylation and prevention of EP300 compensation. These enhancers were enriched for those that are dynamically loaded by CREBBP in the normal centroblast-to-centrocyte transition in the germinal center, including enhancers activated in response to CD40 signaling, leading to blunted molecular response to CD40 ligand in lymphoma cells. We provide evidence that CREBBP KAT-PM inhibits EP300 function by binding limiting quantities nuclear transcription factor, thereby preventing its compensatory activity. This effect can be experimentally overcome by expressing saturating quantities of transcription factor, or biologically attenuated by strong stimulation of CD40 signaling that increases nuclear transcription factor abundance. Importantly, epigenetic responses to CD40 signaling can be induced by enforcing CD4 T-cell engagement using a bispecific antibody, leading to CD40-dependent restoration of antigen presentation machinery in CREBBP KAT-PM cells and cell death. We therefore provide a mechanistic basis for enhancer deregulation by CREBBP KAT-PM and highlight enforced CD4 T-cell engagement as a potential approach for overcoming these effects.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell panleukemia signatures of HSPC-like blasts predict drug response and clinical outcome.","authors":"Changya Chen, Jason Xu, Jonathan H Sussman, Tiffaney L Vincent, Joseph S Tumulty, Satoshi Yoshimura, Fatemeh Alikarami, Wenbao Yu, Yang-Yang Ding, Chia-Hui Chen, Elizabeth Y Li, Austin Yang, Xiaohuan Qin, Shovik Bandyopadhyay, Jacqueline Jiahui Peng, Petri Pölönen, Haley Newman, Brent Wood, Jianzhong Hu, Rawan Shraim, Andrew D Hughes, Caroline Diorio, Lahari Uppuluri, Gongping Shi, Theresa Ryan, Tori Fuller, Mignon L Loh, Elizabeth A Raetz, Stephen P Hunger, Stanley B Pounds, Charles G Mullighan, David Frank, Jun J Yang, Kathrin Maria Bernt, David Trent Teachey, Kai Tan","doi":"10.1182/blood.2024027270","DOIUrl":"10.1182/blood.2024027270","url":null,"abstract":"<p><p>The critical role of leukemic initiating cells as a therapy-resistant population in myeloid leukemia is well established, however, the molecular signatures of such cells in acute lymphoblastic leukemia remain underexplored. Moreover, their role in therapy response and patient prognosis is yet to be systematically investigated across various types of acute leukemia. We employed single-cell multiomics to analyze diagnostic specimens from 96 pediatric patients with acute lymphoblastic, myeloid, and lineage ambiguous leukemias. Through the integration of single-cell multiomics with extensive bulk RNA-Seq and clinical datasets, we uncovered a prevalent, chemotherapy-resistant subpopulation that resembles hematopoietic stem and progenitor cells (HSPC-like) and is associated with poor clinical outcomes across all subtypes investigated. We identified a core transcriptional regulatory network (TRN) in HSPC-like blasts that is combinatorically controlled by HOXA/AP1/CEBPA. This TRN signature can predict chemotherapy response and long-term clinical outcomes. We identified shared potential therapeutic targets against HSPC-like blasts, including FLT3, BCL2, and the PI3K pathway. Our study provides a framework for linking intra-tumoral heterogeneity with therapy response, patient outcome and discovery of new therapeutic targets for pediatric acute leukemias.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biology as vulnerability in follicular lymphoma: genetics, epigenetics, and immunogenetics.","authors":"Ferran Araujo-Ayala, Wendy Béguelin","doi":"10.1182/blood.2024026020","DOIUrl":"10.1182/blood.2024026020","url":null,"abstract":"<p><p>Follicular lymphoma (FL) represents a heterogeneous group of B-cell neoplasms with distinct genetic, epigenetic, microenvironmental, and clinical features. It is the most prevalent indolent non-Hodgkin lymphoma, characterized by a relapsing course and risk of transformation to aggressive diffuse large B-cell lymphoma. Recent advances in high-throughput sequencing, spatial transcriptomics, and imaging technologies uncovered genetic, epigenetic, and immunogenetic features underpinning FL, offering insights into its biology and potential therapeutic vulnerabilities. While FL is primarily driven by the hallmark t(14;18) translocation involving BCL2, its pathogenesis requires additional oncogenic mutations, particularly in genes regulating chromatin and histone modifications. These early genetic and epigenetic alterations promote the persistence and evolution of cancer precursor cells, setting the stage for lymphomagenesis. The tumor microenvironment is also crucial in FL progression and patient prognosis, with T-cells, stromal cells, and macrophages playing pivotal roles in facilitating tumor immune escape. Targeted therapies, including BCL2 inhibitors, epigenetic modulators, and immunotherapies, have emerged from this deeper understanding of FL biology. Achieving a cure for FL will require targeted therapies that selectively eliminate cancer precursor cells with minimal impact on normal cells, thus preventing relapse and avoiding harmful side effects. Eradicating minimal-residual-disease should be a primary objective rather than waiting for clinical relapse. Future research must prioritize the development of accurate experimental models, the elucidation of FL precursors, and a deeper understanding of its heterogeneity, dependencies, progression, and mechanisms driving transformation. Implementing targeted therapies at FL early stages, instead of the current \"watch and wait\" approach, will be essential to improve patient outcomes.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639630","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Loss of BCL7A Permits IRF4 Transcriptional Activity and Cellular Growth in Multiple Myeloma.","authors":"Chandraditya Chakraborty, Srikanth Talluri, Moritz Binder, Eugenio Morelli, Jessica Encinas Mayoral, Sanika Derebail, Anil Aktas Samur, Charles B Epstein, Kenneth C Anderson, Masood A Shammas, Mehmet K Samur, Mariateresa Fulciniti, Nikhil C Munshi","doi":"10.1182/blood.2024026588","DOIUrl":"https://doi.org/10.1182/blood.2024026588","url":null,"abstract":"<p><p>Multiple myeloma (MM) is a complex hematological malignancy characterized by genomic changes and transcriptomic dysregulation. Initial exome sequencing approaches have failed to identify any single frequent (>25%) mutation in the coding genome. However, using whole-genome sequencing (WGS), we found that one of the genomic regions most frequently mutated (62% of the MM patients) was the 5' untranslated (UTR) region and/or intron 1 of the BCL7A gene. RNA-seq data from a large cohort suggests a loss of BCL7A expression in a large majority of MM patients as compared to normal plasma cells. BCL7A loss of function in a panel of MM cell lines led to a highly proliferative phenotype in vitro and in vivo, while its ectopic expression significantly reduced cell viability, suggesting a tumor suppressor function for BCL7A in MM. We studied the cellular and molecular effects of BCL7A loss and observed that it endows myeloma cells with proliferative potential in cooperation with the plasma cell-defining transcription factor IRF4. BCL7A is involved in a direct protein-protein interaction with IRF4, limiting its DNA binding activity. Loss of BCL7A thus enhances the expression of IRF4-associated cytokines and reduces mitochondrial metabolism and ROS levels. Our study therefore suggests that BCL7A loss provides the necessary molecular change to allow IRF4-mediated transcriptional activity and MM cell growth and survival.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Therapeutic switch from plasma to recombinant ADAMTS13 for patients with congenital TTP from Japanese real-world data.","authors":"Kazuya Sakai, Atsushi Hamamura, Yoshiko Yoshimura, Miyuki Abe, Yoshiyuki Ogawa, Kazuki Tanaka, Norimichi Hattori, Tazuko Tokugawa, Rie Kanai, Fumiyoshi Ikejiri, Masahiro Takeyama, Teruhisa Taoka, Naoki Fujita, Minoru Kanaya, Katsuyoshi Koh, Hiroshi Shiragami, Hidekazu Azumi, Kenki Saito, Masanori Matsumoto","doi":"10.1182/blood.2024027516","DOIUrl":"10.1182/blood.2024027516","url":null,"abstract":"<p><p>Congenital thrombotic thrombocytopenic purpura (cTTP) is an ultra-rare disorder characterized by thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ damage caused by pathogenic ADAMTS13 variants. ADAMTS13 containing product including fresh frozen plasma (FFP) and plasma-derived Factor VIII concentrates are commonly used to supply ADAMTS13; however, frequent hospital visits and allergic reactions are major drawbacks. A recombinant ADAMTS13 (rADAMTS13) was recently developed to address these issues. However, real-world evidence has not been reported owing to the rarity of this condition. This study compared the efficacy and safety of FFP and rADAMTS13 in 14 Japanese patients, including five patients with end-stage renal disease who were excluded from the phase III trial. The median peak level of ADAMTS13 activity 15 min after rADAMTS13 administration was significantly higher than that after FFP (68.4% vs. 15.9%, p<0.001). ADAMTS13 activity 1 week after rADAMTS13 administration was well maintained compared with FFP infusion (11.6% vs. 5.1%, p<0.001). Patients reported no allergic reactions after rADAMTS13 administration and appreciated the convenience of a single infusion of rADAMTS13, suggesting that rADAMTS13 is a safe and effective alternative to FFP in patients with cTTP. This is the first publication of patients with cTTP who switched FFP to novel rADAMTS13 from Japanese real-world-data.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639671","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic and epigenetic mechanisms of GPRC5D loss after anti-GPRC5D CAR T-cell therapy in multiple myeloma.","authors":"Sha Ma, Jieyun Xia, Miao Zhang, Wenyu Li, Meng Xiao, Yuqian Sha, Wenya Wang, Jianteng Zhou, Ying Wang, Kunming Qi, Chunling Fu, Zengtian Sun, Dian Zhou, Qian Sun, Tingting Qiu, Zhiling Yan, Feng Zhu, Wei Chen, Hai Cheng, Wei Sang, Jiang Cao, Depeng Li, Zhenyu Zhen Li, Mariateresa Fulciniti, Yao Yao, Kailin Xu, Mingshan Niu","doi":"10.1182/blood.2024026622","DOIUrl":"https://doi.org/10.1182/blood.2024026622","url":null,"abstract":"<p><p>G protein-coupled receptor, class C, group 5, member D (GPRC5D) has emerged as a novel target for chimeric antigen receptor (CAR) T-cell therapy, demonstrating promising efficacy in multiple myeloma (MM). However, disease relapse is still common, and the mechanism of resistance remains poorly understood. In this study, we conducted whole-genome sequencing (WGS) and whole-genome bisulfite sequencing (WGBS) on MM samples from 10 patients who relapsed after GPRC5D CAR T-cell therapy. Among these patients, 8 had GPRC5D loss, while 2 presented mixed expression (GPRC5D+/-). Genetic alterations were identified in three cases: one had a homozygous deletion in the GPRC5D gene, another had a biallelic loss in the regulatory regions of GPRC5D, and the third had homozygous deletions in both TNFRSF17 and GPRC5D after sequential anti-BCMA and anti-GPRC5D CAR T-cell therapies. No genetic changes were detected at GPRC5D locus in the remaining 7 cases. However, multiple hypermethylation sites were present in the transcriptional regulatory elements of the GPRC5D gene in 5 post-treatment MM samples. In MM cell lines, GPRC5D expression was inversely correlated with methylation levels in its regulatory regions. Furthermore, azacitidine treatment induced GPRC5D mRNA and protein expression in hypermethylated MM cell lines. Our findings highlight that biallelic genetic inactivation and hypermethylation-driven epigenetic silencing are key mechanisms contributing to GPRC5D loss and treatment resistance.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteostasis Disruption in Inherited Bone Marrow Failure Syndromes.","authors":"Helena Yu, Robert Signer","doi":"10.1182/blood.2024024956","DOIUrl":"https://doi.org/10.1182/blood.2024024956","url":null,"abstract":"<p><p>Inherited bone marrow failure syndromes (IBMFS) are genetic disorders of impaired hematopoiesis that manifest in childhood with both cytopenias and extra-hematologic findings. While several IBMFS are categorized as ribosomopathies due to shared underlying ribosomal dysfunction, there is a broader disruption of the protein homeostasis (proteostasis) network across both classic and emerging IBMFS. Precise regulation of the proteostasis network, including mechanisms of protein synthesis, folding, trafficking, and degradation as well as associated stress response pathways, has emerged as essential for maintaining hematopoietic stem cell (HSC) function, providing new potential mechanistic insights into IBMFS pathogenesis. Furthermore, the varied clinical trajectories of patients with IBMFS with possible divergent outcomes of malignancy and spontaneous remission may reflect developmental and temporal changes in proteostasis activity and be driven by strong selective pressures to restore proteostasis. These new insights are spurring fresh therapeutic approaches to target proteostasis. Thus, further evaluation of proteostasis regulation and the consequences of proteostasis disruption in IBMFS could aid in developing new biomarkers, therapeutic agents, and preventative approaches for patients.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639665","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Itacitinib for the Prevention of IEC Therapy-Associated CRS: Results From the Two-Part Phase 2 INCB 39110-211 Study.","authors":"Matthew J Frigault, Richard T Maziarz, Jae H Park, Aleksandr Lazaryan, Nirav N Shah, Jakub Svoboda, Lazaros J Lekakis, Ran Reshef, Christine L Phillips, Lea Burke, Jing Lei, Michael Pratta, Rodica Morariu-Zamfir, John F DiPersio","doi":"10.1182/blood.2024026586","DOIUrl":"https://doi.org/10.1182/blood.2024026586","url":null,"abstract":"<p><p>Cytokine release syndrome (CRS) and immune effector cell (IEC)-associated neurotoxicity syndrome (ICANS) are common complications following IEC therapy for hematologic malignancies. This two-part, phase 2 study (INCB 39110-211) investigated safety and efficacy of itacitinib, a potent, highly selective Janus kinase 1 inhibitor with broad anti-inflammatory activity, for prevention of CRS and ICANS in patients receiving commercial CD19-directed IEC therapy. Patients in part 1 received once-daily itacitinib 200 mg 3 days before IEC therapy (axicabtagene ciloleucel [axi-cel], brexucabtagene autoleucel, or tisagenlecleucel) through Day 26, with guidelines for use of other CRS/ICANS interventions. In part 2 (double-blind), patients were randomized to receive twice-daily (bid) itacitinib 200 mg or placebo 3 days before IEC therapy with axi-cel. The primary endpoint was proportion of patients with CRS grade ≥2 by Day 14 using ASTCT consensus grading system. Overall, 111 patients were enrolled (63 in part 1; 48 in part 2), with 109 patients analyzed for efficacy and 110 for safety. Itacitinib 200 mg bid resulted in a significantly lower proportion of patients with grade ≥2 CRS by Day 14 versus placebo (17.4% vs 56.5%; P=0.003). The proportion of patients with grade ≥2 ICANS by Day 28 was lower than with placebo (8.7% vs 21.7%). Itacitinib was well tolerated, with pyrexia the most common TEAE (itacitinib 200 mg bid: 43.5%; placebo: 50.0%) and itacitinib-related cytopenias manageable. Importantly, itacitinib did not impact IEC therapy efficacy (objective response rate at 6 months: 39.1% for itacitinib 200 mg bid vs 26.1% for placebo). Trial registration: clinicaltrials.gov; #NCT04071366.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A TIM-3-Fc decoy secreted by engineered T cells improves CD19 CAR-T cell therapy in B-cell acute lymphoblastic leukemia.","authors":"Aïda Falgàs, Rodrigo Lázaro-Gorines, Samanta Romina Zanetti, Laura Rubio-Pérez, Alba Martinez-Moreno, Meritxell Vinyoles, Mercedes Guerrero-Murillo, Narcís Fernandez-Fuentes, Heleia Roca-Ho, Néstor Tirado, Carla Panisello, Talía Velasco-Hernandez, Andrea Mayado, Alba Pérez-Pons, Eulalia Genesca, Josep-Maria Ribera, Jordi Ribera, Mireia Camos, Manuel Ramírez-Orellana, Eduardo Anguita, Paola Ballerini, José Luis Fuster, Manel Juan, Europa Azucena Azucena González-Navarro, Franco Locatelli, Ronald W W Stam, Sergio Querol, Pablo Velasco, Valentín Ortiz-Maldonado, Nuria Martínez-Cibrian, Julio Delgado, Alberto Orfao, Luis Alvarez-Vallina, Clara Bueno, Pablo Menendez","doi":"10.1182/blood.2024025440","DOIUrl":"10.1182/blood.2024025440","url":null,"abstract":"<p><p>Relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) remains a challenging disease with a dismal prognosis. Despite the revolutionary impact of CD19-directed chimeric antigen receptor (CAR19)-T cell therapy, >50% of patients relapse within a year. Both leukemia cell-intrinsic factors favoring immune escape and poor CAR-T cell persistence contribute significantly to clinical failure. Moreover, the expression of immune checkpoint receptors (ICRs) and their ligands within the complex bone marrow (BM) microenvironment may contribute to leukemia progression and therapy resistance. Here, we comprehensively characterized the expression of ICRs and their ligands in leukemic blasts, T cells, and mesenchymal stromal cells (MSCs) from B-ALL BM samples at diagnosis (n=47) and relapse (n=38), comparing them with age-matched healthy BM controls. Our findings reveal a significant upregulated expression of TIM-3 in T cells, and its ligand galectin-9 in both blasts and MSCs throughout disease progression. The expression levels of galectin-9 in B-ALL blasts and TIM-3 in CAR19-T cells negatively correlate with clinical outcome. Furthermore, we demonstrate that galectin-9 impairs CAR19-T cell homeostasis and cytotoxicity. Notably, an engineered TIM-3-Fc decoy receptor, delivered either by primary T cells co-administered with CAR19-T cells or via a bicistronic all-in-one CAR19-TIM-3-Fc construct, improved the anti-leukemia efficacy and persistence of CAR19-T cells in B-ALL patient-derived xenograft models. Mechanistically, CAR19-TIM-3-Fc-T cell treatment promotes the in vivo expansion of both transduced and bystander effector and memory T cells, as determined by spectral flow cytometry. Collectively, these potent and persistent TIM-3-Fc decoy-armored CAR19-T cells offer a promising therapeutic strategy for R/R B-ALL patients.</p>","PeriodicalId":9102,"journal":{"name":"Blood","volume":" ","pages":""},"PeriodicalIF":21.0,"publicationDate":"2025-03-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143639611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}