Seminars in hematology最新文献

{"title":"Repositioning neutrophils in cancer immunotherapy: From innate defenders to antibody-driven effectors.","authors":"Jisun Lee, Bomi Kim, Sang Taek Jung","doi":"10.1053/j.seminhematol.2025.12.003","DOIUrl":"10.1053/j.seminhematol.2025.12.003","url":null,"abstract":"<p><p>Neutrophils, the most abundant innate immune cell population in human circulation, serve as frontline defenders through canonical mechanisms including degranulation, generation of reactive oxygen species (ROS), and neutrophil extracellular trap (NET) formation. Beyond their classical antimicrobial functions, emerging evidence positions neutrophils as critical effectors in antibody-based cancer immunotherapy. Through Fc receptor-mediated mechanisms, such as antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and trogocytosis, as well as strategies engaging the IgA-FcαRI (CD89) axis, neutrophils elicit enhanced antitumor responses compared to conventional IgG-based modalities. Building upon this framework, therapeutic approaches have progressed from granulocyte colony-stimulating factor (G-CSF)-mediated neutrophil expansion to bispecific antibody platforms that actively redirect neutrophils toward tumor cells, with proof-of-concept established in hematologic malignancies through CD89-targeting bispecific formats. However, in solid tumors, the immunosuppressive tumor microenvironment (TME) and skewing toward a protumorigenic N2 phenotype substantially hinder neutrophil-mediated cytotoxicity. To overcome these limitations, recent efforts have focused on reprogramming neutrophil functions through TGF-β blockade and rational immunotherapeutic combinations. Collectively, these integrative strategies offer the potential to reposition neutrophils from classical innate immune sentinels to dynamic effectors in antibody-based cancer immunotherapy.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"342-349"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146012043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Engineering the Next Generation of Antibody Therapeutics in Hematology.","authors":"Junho Chung","doi":"10.1053/j.seminhematol.2026.01.001","DOIUrl":"https://doi.org/10.1053/j.seminhematol.2026.01.001","url":null,"abstract":"","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 4","pages":"243-244"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147469111","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The emergence of a new paradigm with signal 1 and signal 2 T-cell engagers in hematology.","authors":"Hayoung Kwon, Chang-Han Lee","doi":"10.1053/j.seminhematol.2025.11.005","DOIUrl":"10.1053/j.seminhematol.2025.11.005","url":null,"abstract":"<p><p>First-generation T-cell engagers have demonstrated significant efficacy in treating hematological malignancies by providing a potent T-cell receptor Signal 1. However, their efficacy is limited by the absence of a TCR co-stimulatory Signal 2, which results in T-cell exhaustion and resistance. A new strategy that addresses this issue is the use of bispecific antibodies (bsAbs) that target co-stimulatory Signal 2. These bispecific antibodies (bsAbs) co-engage a cancer-associated antigen (CAA) with a T-cell co-stimulatory receptor, such as CD28 or 4-1BB. Recent clinical strategies have combined Signal 1 and Signal 2 engagers in dual-bispecific regimens for lymphoma and multiple myeloma treatment. Therefore, the \"Signal 1 + Signal 2\" approach represents a significant advancement in immunotherapy, offering the potential to achieve deeper responses, overcome drug resistance and establish a robust 'off-the-shelf' therapeutic platform.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"245-254"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting B-cell maturation antigen in relapsed or refractory multiple myeloma: On the verge of its prime time.","authors":"Jun Ho Yi, Dok Hyun Yoon, Kihyun Kim","doi":"10.1053/j.seminhematol.2025.11.003","DOIUrl":"10.1053/j.seminhematol.2025.11.003","url":null,"abstract":"<p><p>Significant advances have been made in the treatment of multiple myeloma, with B-cell maturation antigen (BCMA)-targeting immunotherapies at the forefront of these developments. Three treatment modalities-including antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor-T cell therapies-have demonstrated durable responses, each associated with class-specific unique adverse events. Moreover, their efficacy and safety in later stages of multiple myeloma also provide the rationale for their use in earlier lines of therapy. In this review, we briefly outline the background biology of BCMA and discuss the mechanisms of action and structural features of these 3 agents, together with the most recent clinical data from early-phase trials. We also describe class-specific adverse events and mechanisms of resistance, as well as strategies to overcome them, thereby offering a framework to catch up with future developments in BCMA-targeted immunotherapy for multiple myeloma.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"305-318"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757647","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances and challenges in CAR-T therapy for glioblastoma.","authors":"Hyeri Ryou, Sang-Eun Jung, Hyungseok Seo","doi":"10.1053/j.seminhematol.2025.12.001","DOIUrl":"10.1053/j.seminhematol.2025.12.001","url":null,"abstract":"<p><p>Glioblastoma (GBM) remains one of the most lethal primary brain tumors, with current standard therapies conferring only limited survival benefit. Although immunotherapeutic approaches have expanded treatment options, they have yet to demonstrate consistent and durable efficacy. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising platform with the potential to overcome critical limitations of existing strategies. This review highlights the unique advantages of CAR-T therapy in complementing both standard and immune-based treatments. It further summarizes clinical outcomes reported to date, encompassing completed and ongoing trials, and underscores recurring barriers such as antigen heterogeneity, limited persistence, and the profoundly immunosuppressive tumor microenvironment. In view of these challenges, we discuss emerging strategies to advance CAR-T therapy in GBM, including approaches to broaden antigen recognition, enhance effector function, improve safety, and explore alternative cellular platforms. With continued innovation and rigorous clinical evaluation, CAR-T therapy holds considerable promise for delivering meaningful and durable benefit to patients with GBM.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"319-332"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145889850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BCMA biology and therapeutic targeting in multiple myeloma: From ligand signaling to antigen escape.","authors":"Ebru Sezer, Seungyoun Lee, Junho Chung","doi":"10.1053/j.seminhematol.2025.12.004","DOIUrl":"10.1053/j.seminhematol.2025.12.004","url":null,"abstract":"<p><p>B-cell maturation antigen (BCMA; TNFRSF17) has rapidly evolved from a plasma cell survival receptor within the BAFF/APRIL network to a central therapeutic hub in multiple myeloma (MM). In this review, we first outline the gene organization, expression pattern, and ligand biology of BCMA in the context of its sister receptors BAFF-R and TACI, emphasizing shared structural motifs-such as the conserved helix-loop-helix hairpin and DxL motif-that govern APRIL/BAFF recognition. We next detail how BCMA-proximal signaling through TRAF adaptors integrates canonical and noncanonical NF-κB, MAPK, and PI3K-AKT pathways to sustain long-lived plasma cells and drive myeloma progression, and how γ-secretase-mediated shedding generates soluble BCMA (sBCMA), which function as both a dynamic disease biomarker and an antigen sink for BCMA-directed agents. We then summarize the clinical development and distinguishing features of currently approved BCMA-targeted modalities-CAR T-cell therapies (ide-cel, cilta-cel), bispecific T-cell engagers (teclistamab, elranatamab, linvoseltamab), and the antibody-drug conjugate (belantamab mafodotin)-highlighting their efficacy, toxicity profiles, and practical positioning in relapsed/refractory MM. Finally, we review emerging resistance mechanisms, including γ-secretase-driven sBCMA elevation, ligand-rich APRIL/BAFF niches, and therapy-induced TNFRSF17 lesions, ranging from biallelic deletions to epitope-altering missense mutations and in-frame deletions within the BCMA extracellular domain. These insights inform rational strategies such as γ-secretase inhibition, dual-target CAR T-cells and bispecific T-cell engagers.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"267-278"},"PeriodicalIF":4.3,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145990654","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Harnessing single-domain antibodies for CAR-T and bispecific antibody development.","authors":"Mooyoung Jung, Jeong Yeon Hwang, Hyunbo Shim","doi":"10.1053/j.seminhematol.2025.11.001","DOIUrl":"10.1053/j.seminhematol.2025.11.001","url":null,"abstract":"<p><p>Emerging antibody-based therapeutic modalities such as CAR-Ts and bispecific antibodies have proven highly efficacious in treating diseases, including hematological malignancies. However, the complex molecular architectures of these novel agents present significant challenges in their design and production, for which binding moieties with small size and favorable physicochemical properties may offer a promising solution. Single domain antibodies (sdAbs), typically derived from the heavy chain antibodies of camelids and cartilaginous fishes but increasingly from synthetic and other sources as well, are small (12-15 kDa), well expressed, and exhibit favorable physicochemical properties, making them ideal targeting domains for these new modalities. In this article, we review the origins and characteristics of sdAbs, along with recent studies on CAR-T cell therapies and bispecific antibodies for hematological malignancies that incorporate sdAbs into their constructs, with emphasis on their structures, binding properties, and therapeutic efficacies. Together, these developments underscore the promise of sdAb-based CAR-Ts and bispecific antibodies as next-generation therapeutics, with the potential to expand treatment options and improve outcomes in hematological malignancies and beyond.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"333-341"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678778","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trispecific T cell engagers in hematological malignancies: Advancing beyond bispecific antibodies.","authors":"Kyung-Nam Koh, Dae Hee Kim, Hyori Kim","doi":"10.1053/j.seminhematol.2025.11.002","DOIUrl":"10.1053/j.seminhematol.2025.11.002","url":null,"abstract":"<p><p>The success of bispecific T cell engagers (BiTEs) in hematological malignancies has catalyzed the development of trispecific antibodies that simultaneously target 3 molecular entities. These next-generation immunotherapeutics address the key limitations of bispecific constructs including antigen escape, limited T cell activation, and on-target off-tumor toxicity. Trispecific constructs employ 2 primary strategies: dual tumor antigen targeting combined with CD3 engagement to prevent antigen escape, and integration of co-stimulatory signals (CD28, 4-1BB) to enhance T cell function. Early clinical data demonstrated promising efficacy signals, particularly in multiple myeloma where BCMA×CD38×CD3 constructs achieved 90% overall response rates in early-phase trials. Safety profiles mirror bispecific antibodies with cytokine release syndrome and neurotoxicity as primary concerns. Trispecific T cell engagers represent a significant advancement in precision immunotherapy for hematological malignancies. Although early clinical results are encouraging, challenges remain in optimal target selection, manufacturing complexity, and resistance mechanisms. Ongoing clinical trials will define their role in the evolving treatment landscape.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"350-356"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145782552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of anti-CD3 antibodies in clinically available bispecific T cell engagers.","authors":"Hyeonmin Lee, Yonghee Lee, Junho Chung","doi":"10.1053/j.seminhematol.2025.08.004","DOIUrl":"10.1053/j.seminhematol.2025.08.004","url":null,"abstract":"<p><p>Bispecific T cell engagers (bispecific TCEs) are engineered antibodies that redirect T cells to mediate tumor cell killing by simultaneously binding to CD3 on T cells and tumor-associated antigens. As of July 2025, ten bispecific TCEs are clinically available. The CD3-binding antibodies in these bispecific TCEs can be classified into 6 groups based on the amino acid sequence similarity across their 6 complementarity-determining regions (CDRs). Specifically, antibodies were assigned to the same family if their six CDRs-HCDR1-3 and LCDR1-3-exhibited ≥80% pairwise sequence identity upon multiple sequence alignment. Family 1, derived from OKT3-a mouse hybridoma generated by immunizing BALB/c mice with human T cells-includes only blinatumomab; Family 2, derived from SP34-a rhesus monkey (Macaca mulatta) derived hybridoma specific for human T cells-comprises 5 antibodies; and Family 6, derived from UCHT1-a mouse hybridoma generated by immunizing mice with human T cells-contains only tebentafusp. The origin of the remaining 3 antibodies has not been disclosed and they possess unique CD3-binding sequences. We classified them into their own distinct families (Families 3, 4, and 5). Interestingly, mosunetuzumab (Family 4) showed remarkably lower incidence of adverse events such as cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and infection compared to other bispecific TCEs even though its affinity for CD3ε was not significantly different. The epitopes of 4 antibodies in Family 2, teclistamab, talquetamab, glofitamab, and tarlatamab were previously defined to be located at the N-terminal region of CD3ε via hydrogen-deuterium exchange mass spectrometry (HDX-MS) analysis. In our in silico epitope prediction analysis, the N-terminal region was included in the epitope region of all bispecific TCEs regardless of their family. Blinatumomab (Family 1) and tebentafusp (Family 6) did not bind to the CD3ε homolog of the cynomolgus monkey, whereas the other 8 bispecific TCEs did. This lack of cross-reactivity poses clear disadvantages in their preclinical development, particularly for toxicity and safety evaluation in nonhuman primate models.</p>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":" ","pages":"279-288"},"PeriodicalIF":4.1,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Measurable residual disease monitoring in acute myeloid leukaemia: Techniques, timing and therapeutic implications","authors":"Kasper J. Croese ,&nbsp;Jacqueline Cloos ,&nbsp;Jesse M. Tettero","doi":"10.1053/j.seminhematol.2025.06.004","DOIUrl":"10.1053/j.seminhematol.2025.06.004","url":null,"abstract":"<div><div>The detection of measurable residual disease (MRD) in acute myeloid leukaemia (AML) has emerged as one of the strongest prognostic indications of adverse outcomes across different treatment settings and disease stages, independent of baseline genetic risk classification. Multiple techniques for MRD-assessment have been developed and clinically validated, including multiparameter flow cytometry (MFC) and molecular assays such as quantitative PCR (qPCR) and next-generation sequencing (NGS). These approaches have been incorporated into routine clinical practice to evaluate treatment efficacy and refine disease risk stratification. Beyond the prognostic significance, MRD monitoring offers a powerful tool for monitoring subclinical disease, enabling early relapse detection and influencing therapeutic decisions, including consolidation strategies, transplant conditioning, and pre-emptive interventions. In non-intensive treatment settings, MRD may help tailor treatment duration and identify patients eligible for therapy cessation. As the therapeutic landscape of AML continues to evolve with novel agents and strategies, the role and clinical applications of MRD are becoming increasingly relevant. This review summarizes current MRD assessment techniques, optimal measurement timepoints, and clinical applications across different therapeutic settings. We also highlight ongoing innovations and future directions that aim to fully integrate MRD into precision management of patients with AML.</div></div>","PeriodicalId":21684,"journal":{"name":"Seminars in hematology","volume":"62 3","pages":"Pages 167-176"},"PeriodicalIF":4.1,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}