Blood Cancer Discovery最新文献

{"title":"Tumor-Infiltrating Clonal Hematopoiesis Is Associated with Adverse Clinical Outcomes in Diffuse Large B-cell Lymphoma.","authors":"Jiahao Chen, Xiao-Yu Wu, Xiang Li, Qing Shi, Di Fu, Yun-Ruei Kao, Yan Zhu, Bo-En Wang, Hao-Xing Bian, Yan Zhao, Yun Tan, Li Wang, Peng-Peng Xu, Wei-Li Zhao","doi":"10.1158/2643-3230.BCD-25-0191","DOIUrl":"10.1158/2643-3230.BCD-25-0191","url":null,"abstract":"<p><p>Tumor-infiltrating clonal hematopoiesis (TI-CH) contributes to the progression of nonhematologic cancers. CH is prevalent in the peripheral blood of patients with diffuse large B-cell lymphoma (DLBCL), but TI-CH prevalence and clinical relevance remain largely unexplored. In this study, through genome- and exome-wide sequencing of DLBCL biopsies and blood samples from 304 treatment-naïve patients, we identified TI-CH in 13.5% of cases, which emerged as an independent risk indicator for disease progression and death. TI-CH cases had an enrichment of inflammatory myeloid signatures revealed by gene expression profiling of tumor biopsies. In addition, we developed a TI-CH-associated prognostic signature (CAPS) based on 24 differentially expressed genes. A high CAPS score correlated with poor survival across four patient cohorts and remained significant in three cohorts after adjustment for patient age, sex, International Prognostic Index score, and cell-of-origin classification. Collectively, these findings establish a link between TI-CH and clinical outcomes and implicate the inflammatory signature as the potential underlying basis.</p><p><strong>Significance: </strong>TI-CH correlates with disease progression and death in patients and with the inflammatory modeling of the DLBCL tumor microenvironment. Our results underscore the clinical and biological relevance of TI-CH and suggest its potential as a biomarker for risk stratification and as a target for therapeutic intervention in DLBCL.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"726-741"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148319495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BTK Degraders in Lymphoid Malignancies: New Modality, New Resistance Rules?","authors":"Alberto J Arribas, Carlo Visco, Francesco Bertoni","doi":"10.1158/2643-3230.BCD-26-0162","DOIUrl":"10.1158/2643-3230.BCD-26-0162","url":null,"abstract":"<p><p>After more than a decade of clinical experience with Bruton tyrosine kinase (BTK) inhibitors, resistance to BTK targeting has become a moving target, shaped by drug-specific BTK mutations, downstream signaling escape, and disease-dependent adaptive programs. The arrival of BTK degraders introduces a mechanistically distinct modality for lymphoid malignancies but also raises a timely question: does degrading BTK rewrite the rules of resistance or simply redraw its boundaries?</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"658-663"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hattrick against Lymphoma with Trispecific CAR T Cells.","authors":"Maximilian Merz, Efrat Luttwak","doi":"10.1158/2643-3230.BCD-26-0257","DOIUrl":"10.1158/2643-3230.BCD-26-0257","url":null,"abstract":"<p><p>Vasu and colleagues report one of the first clinical evaluations of rapidly manufactured trispecific chimeric antigen receptor T cells targeting CD19, CD20, and CD22. The lymphoma efficacy signal and favorable observed safety profile support further investigation, whereas the correlative analyses suggest that baseline T-cell fitness and early post-infusion functional states may remain important determinants of outcome. See related article by Vasu et al., p. 711.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"652-654"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148702446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CAR T Cells Targeting an Intracellular Leukemia Antigen Promiscuously Presented by Diverse HLA-II Alleles.","authors":"Evey Y F Zheng, Chung-Hsi Wang, Toshiki Ochi, Yota Ohashi, Fumie Ihara, Saori Fukao, Yusuke Ito, Giselle M Boukhaled, Ben X Wang, Dong-Hoon Han, Xinyu Wei, Priyanka Yolmo, Brian D Burt, Kayoko Saso, Yukiko Matsunaga, Dalam Ly, Yuki Kagoya, Marcus O Butler, Mark D Minden, Naoto Hirano","doi":"10.1158/2643-3230.BCD-25-0230","DOIUrl":"10.1158/2643-3230.BCD-25-0230","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) technology has revolutionized B-cell malignancy treatment by enabling T cells to effectively recognize and target lineage-specific surface antigens. However, CAR T cells show limited efficacy against myeloid neoplasms and solid tumors due to challenges in identifying suitable surface targets. In this study, we present a CAR targeting the intracellular WT1 oncoprotein, cross-presented by surface HLA class II (HLA-II) alleles. WT1-CAR T cells, derived from an antibody raised solely against a WT1 peptide, recognized the WT1330-348 peptide promiscuously presented by 18 out of 20 tested HLA-II alleles, overcoming traditional HLA restrictions. WT1-CAR T cells specifically recognized leukemic cells in a WT1- and HLA-II-dependent manner and mediated an antitumor response in vitro and in vivo. This approach broadens CAR-targetable antigens beyond traditional HLA restrictions and offers a promising therapeutic option to a wide and genetically diverse patient population.</p><p><strong>Significance: </strong>Leveraging the promiscuous binding of HLA-II-peptide complexes, we developed a CAR T-cell approach targeting an intracellular oncoprotein WT1 presented across diverse HLA-II families. Our study establishes a framework for CAR therapies against intracellular antigens, extending potential CAR T-cell applications to new cancer types and patient populations.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"813-828"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148762029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Germline noncoding risk variants influence clonal hematopoiesis through altered hematopoietic enhancer activity.","authors":"Trieu Nguyen, Jessica Jeejan, Takeshi Iwasaki, Susan Kales, Joyeeta Chakraborty, Chie Yanase, Aruna Shekhar, Dominika Kwasniak, Aditi Hegde, Richard Voit, Joshua Weinstock, Kristy R Stengel, Keisuke Ito, Ryan Tewhey, Satish K Nandakumar","doi":"10.1158/2643-3230.BCD-26-0046","DOIUrl":"10.1158/2643-3230.BCD-26-0046","url":null,"abstract":"<p><p>Clonal hematopoiesis of indeterminate potential (CHIP) is a precursor condition characterized by the expansion of mutant hematopoietic stem and progenitor cell (HSPC) clones that increases the risk of hematologic malignancies. Although genome-wide association studies have identified multiple non-coding loci associated with CHIP susceptibility, their mechanisms remain unclear. We hypothesized that CHIP risk variants alter enhancer activity in HSPCs. To test this, we screened 1,374 non-coding variants from 51 CHIP-associated loci using a Massively Parallel Reporter Assay (MPRA) in the CD34+ fraction of MUTZ-3 cells. We identified 87 regulatory variants across 32 loci. Targeted genome editing in hematopoietic cells and complementary reporter assays in primary human HSPCs validated enhancer activity for variants regulating NKD2, FLT3, and MSI2. Functional studies demonstrated that increased MSI2 expression, modeling the effect of the CHIP risk allele, promotes clonal expansion of TET2-deficient HSPCs, providing a mechanistic link between inherited non-coding variation and CHIP clonal expansion.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148888313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Living Archive of High-risk Lymphoma.","authors":"Laura Evgin, Christian Steidl","doi":"10.1158/2643-3230.BCD-26-0250","DOIUrl":"10.1158/2643-3230.BCD-26-0250","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Yang and colleagues present a comprehensive repository of patient-derived xenograft models of aggressive large B-cell lymphoma. The publicly available resource links disease specimens from individuals treated with diverse modern therapies (including chimeric antigen receptor T cells) to their high-risk clinical treatment histories and the molecular and transcriptional characteristics of their tumors, enabling the study of tumor cell-intrinsic mechanisms of therapeutic resistance and susceptibility to novel therapies. See related article by Yang et al., p. 829.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"655-657"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148702502","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Predictive Models for Toxicities after CAR T-cell Therapy: Challenges and Opportunities.","authors":"Julie Ma, August Culbert, Tian-Gen Chang, Mark L Solter, Eytan Ruppin, Kai Rejeski, Nirali N Shah","doi":"10.1158/2643-3230.BCD-25-0458","DOIUrl":"10.1158/2643-3230.BCD-25-0458","url":null,"abstract":"<p><p>Chimeric antigen receptor (CAR) T-cell therapy is increasingly utilized with expanding indications beyond hematologic malignancies. Here, we review existing models developed for predicting toxicities in the CAR T-cell setting and identify both strengths and challenges emerging with their application. Predictive modeling approaches offer potential to guide risk stratification and inform clinical decision-making, but small sample sizes, overfitting, and poor data quality have limited model reproducibility and widespread adoption. As utilization of CAR T-cell therapy broadens, identifying additional biomarkers, developing context-specific models, standardizing guidelines for emerging toxicities, and leveraging federated learning to promote collaborative data sharing will be critical.</p><p><strong>Significance: </strong>Predictive models integrating biomarkers and clinical variables are increasingly used to forecast potential toxicities after CAR T-cell therapy. However, due to heterogeneity in patient populations and cellular therapy products, the rapidly evolving nature of the field, and continued advancements in management of inflammatory toxicities, modeling in CAR T-cell therapy faces significant challenges. This comprehensive review of existing/emerging models serves to delineate components of developing predictive models including discrimination, calibration, biomarker integration, validation, and mitigation of overfitting while highlighting strengths, opportunities for improvement, and future directions applicable to CAR T-cell therapy.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"664-686"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13463384/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148707807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Outcomes of CAR T-cell Therapy and Bispecific Antibodies as Single-Modality and Sequential Strategies in Relapsed/Refractory Multiple Myeloma.","authors":"Maximilian Merz, Tomas Jelinek, Thomas Pabst, Raphael Teipel, Anca-Maria Albici, Bastian von Tresckow, Marcel Teichert, Uta Margareta Demel, Antonia Busse, Marie Christine Wesener, Tobias A W Holderried, Friederike Schmitz, Friedrich-Linus Rößiger, Fabian Müller, Michele Hoffmann, Friedrich Stölzel, Natalia Tovar, Ben-Niklas Baermann, Martin Stork, Alexandra Jungova, Jiri Minarik, Jakub Radocha, Ivan Spicka, Ludek Pour, Polona Novak, Klara Slajpah, Karla Rener, Ulrich Keller, Stephan Bohl, David Fandrei, Patrick Born, Vladan Vučinić, Nicolaus Kröger, Irene Strassl, Natalie Schub, Roman Hájek, Matjaž Sever, Carlos Fernández de Larrea, Nico Gagelmann","doi":"10.1158/2643-3230.BCD-25-0461","DOIUrl":"10.1158/2643-3230.BCD-25-0461","url":null,"abstract":"<p><p>We explored single or consecutive chimeric antigen receptor (CAR) T and bispecific antibody (BsAb) treatment modalities as correlates of clinical outcomes, by complementary bias-correction analysis of a retrospective multicenter study of 640 patients with relapsed/refractory multiple myeloma. The sequential use of both modalities seemed to yield the most favorable survival trajectories. Initiating treatment with CAR T [idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), cesnicabtagene autoleucel (cesni-cel)] was associated with longer remission. However, mortality from early progression was similar regardless of initial modality, suggesting that resistance may negate initial efficacy difference. On the product level, the benefit of CAR T seemed to be driven by cilta-cel and cesni-cel, whereas BsAbs showed at least comparable outcomes with ide-cel. These exploratory findings highlight the critical importance of treatment sequencing in optimizing long-term outcomes and underscore the need for equitable and timely access to both modalities across healthcare systems.</p><p><strong>Significance: </strong>In this real-world cohort, initiating treatment with CAR T was associated with longer remission, and sequential immunotherapy incorporating both modalities yielded the most favorable outcomes. However, early treatment failure negated initial efficacy differences between modalities. These findings provide a rationale for prospective sequencing trials and equitable access to both treatments. See related commentary by Banerjee, p. 650.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"697-710"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13539189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148240370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LY3410738, a Covalent Inhibitor of Mutant IDH1/2, Is Effective in Acute Myeloid Leukemia Preclinical Models.","authors":"Nathan A Brooks, Anna Skwarska, Vivian Salama, Mark H Bender, Lisa Kays, Robin I DeWalt, Bryan Perria, Deepti Thete, Jason R Manro, Rachel Cavitt, Rebecca Leon, Sandra Gomez, Raquel Torres, John M Strelow, Paul Milligan, Kate Newell, Kenneth D Roth, Jean-Emmanuel Sarry, Steven M Chan, Danalyn Manglicmot Lagutan, Richard Romero, Stephen Antonysamy, Robert L Johnson, Xueqian Gong, Renato A Bauer, Timothy P Burkholder, Patric J Hahn, Zoran Rankovic, Serge L Boulet, Courtney D DiNardo, Marina Konopleva, Raymond Gilmour","doi":"10.1158/2643-3230.BCD-25-0379","DOIUrl":"10.1158/2643-3230.BCD-25-0379","url":null,"abstract":"<p><p>Acute myeloid leukemia (AML) is an aggressive blood disorder characterized by rapid growth of poorly differentiated myeloid cells. Gain-of-function mutations in isocitrate dehydrogenases (IDH) are detected in ∼20% of AML and ∼80% of secondary gliomas. Mutant IDH1/2 isoenzymes acquire neomorphic activity to produce 2-hydroxyglutarate (2-HG) oncometabolite, resulting in hypermethylated DNA and histones, altered gene expression, and blocked differentiation of hematopoietic progenitors. Here, we present preclinical development of LY3410738, an oral, dual IDH1/2 inhibitor with potential to penetrate the blood-brain barrier. LY3410738 covalently inhibited mutated IDH1/2, reduced 2-HG levels at low nanomolar concentrations in human AML and glioma models, and demonstrated efficacy in AML patient-derived xenografts (PDX) in vivo, inducing myeloid differentiation. LY3410738 retained in vitro activity in cancer models with acquired secondary IDH1/2 mutations conferring resistance to ivosidenib and enasidenib. LY3410738 synergized and was well tolerated with standard-of-care regimens such as cytarabine, azacitidine, venetoclax, or midostaurin in IDH1/2-mutated AML PDXs.</p><p><strong>Significance: </strong>LY3410738 represents a promising advancement in the treatment of IDH1/2-mutated AML. Its irreversible binding and targeting of both IDH1/2 isoforms, coupled with sustained activity against mIDH1/2 with acquired second-site resistance mutations, distinguishes LY3410738 from clinically available IDH inhibitors and suggests therapeutic potential for patients with AML resistant to standard IDH-based treatment.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"774-795"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sequenced, Not Stirred: Positioning CAR T and Bispecific Antibody Therapy in Multiple Myeloma.","authors":"Rahul Banerjee","doi":"10.1158/2643-3230.BCD-26-0256","DOIUrl":"10.1158/2643-3230.BCD-26-0256","url":null,"abstract":"<p><p>In this issue of Blood Cancer Discovery, Merz and colleagues study more than 600 recipients of chimeric antigen receptor T-cell (CAR T) and/or bispecific antibody therapy in multiple myeloma with an emphasis on patients who received both modalities sequentially. They find a clear progression-free survival advantage when CAR T therapy was used first; importantly, because outcomes with both modalities were similar when following progression after the converse modality, this advantage was driven by CAR T therapy's up-front benefits. See related article by Merz et al, p. 697.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"650-651"},"PeriodicalIF":12.2,"publicationDate":"2026-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148725045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}