Pub Date : 2025-10-24DOI: 10.1038/s41408-025-01370-1
Weijun Zhou,Jinyi Yu,Fuyu Li,Yuting Huang,Jingwen Du,Anqin Wu,Kankan Wang
Accumulation of genetic mutations in malignant myeloid precursor cells leads to an extremely poor prognosis for patients with acute myeloid leukemia (AML). Immunogenic neoantigens recognized by T cell receptor (TCR) can elicit effective immune responses against malignant cells with corresponding somatic mutations. To broaden the range of targeted treatments for AML, in this study, we explored the feasibility of immunotherapy targeting neoantigens arising from recurrent mutations, which are exclusively present on leukemic cells. We used data-driven methods to select seven neoantigens from four frequently mutated genes (NPM1, FLT3, TP53, and DNMT3A) associated with HLA-A*02:01-positive AML patients. Functional assays demonstrated that neoantigens derived from NPM1/W288fs, FLT3/D835H, and FLT3/D835Y were shown to induce specific T cell responses in AML patients. We further identified the specific TCR sequences from healthy donors capable of recognizing these neoantigens. In-depth studies of their specific T cells revealed the presence of dominant αβTCRs that could specifically recognize NPM1/W288fs and FLT3/D835H in an HLA-A*02:01-restricted manner. T cells engineered with each αβTCR selectively recognized and killed HLA-A*02:01-positive AML targets endogenously expressing corresponding mutations. Overall, our findings support the clinical translation of adoptive neoantigen-specific TCR-engineered T cells as a novel therapeutic strategy for treating AML.
{"title":"Identification of specific T-cell response and T-cell receptor targeting shared neoantigen for acute myeloid leukemia.","authors":"Weijun Zhou,Jinyi Yu,Fuyu Li,Yuting Huang,Jingwen Du,Anqin Wu,Kankan Wang","doi":"10.1038/s41408-025-01370-1","DOIUrl":"https://doi.org/10.1038/s41408-025-01370-1","url":null,"abstract":"Accumulation of genetic mutations in malignant myeloid precursor cells leads to an extremely poor prognosis for patients with acute myeloid leukemia (AML). Immunogenic neoantigens recognized by T cell receptor (TCR) can elicit effective immune responses against malignant cells with corresponding somatic mutations. To broaden the range of targeted treatments for AML, in this study, we explored the feasibility of immunotherapy targeting neoantigens arising from recurrent mutations, which are exclusively present on leukemic cells. We used data-driven methods to select seven neoantigens from four frequently mutated genes (NPM1, FLT3, TP53, and DNMT3A) associated with HLA-A*02:01-positive AML patients. Functional assays demonstrated that neoantigens derived from NPM1/W288fs, FLT3/D835H, and FLT3/D835Y were shown to induce specific T cell responses in AML patients. We further identified the specific TCR sequences from healthy donors capable of recognizing these neoantigens. In-depth studies of their specific T cells revealed the presence of dominant αβTCRs that could specifically recognize NPM1/W288fs and FLT3/D835H in an HLA-A*02:01-restricted manner. T cells engineered with each αβTCR selectively recognized and killed HLA-A*02:01-positive AML targets endogenously expressing corresponding mutations. Overall, our findings support the clinical translation of adoptive neoantigen-specific TCR-engineered T cells as a novel therapeutic strategy for treating AML.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"4 1","pages":"178"},"PeriodicalIF":12.8,"publicationDate":"2025-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145357902","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}
Pub Date : 2025-10-22DOI: 10.1038/s41408-025-01396-5
Sonja Wurm,Jennifer M Moritz,Verena Petzer,Dominik Wolf,Karoline V Gleixner,Wolfgang R Sperr,Christina Groiss,Sigrid Machherndl-Spandl,Gregor Eisenwort,Elisabeth Koller,Johannes Schoeche,Clemens Petrasch,Josef Singer,Daniel M Mayer,Gudrun Pregartner,Annkristin Heine,Albert Wölfler,Heinz Sill,Andreas Reinisch,Armin Zebisch
{"title":"Efficacy assessment following shortened venetoclax exposure in AML patients treated with venetoclax plus hypomethylating agents: a real-world, multicentric study.","authors":"Sonja Wurm,Jennifer M Moritz,Verena Petzer,Dominik Wolf,Karoline V Gleixner,Wolfgang R Sperr,Christina Groiss,Sigrid Machherndl-Spandl,Gregor Eisenwort,Elisabeth Koller,Johannes Schoeche,Clemens Petrasch,Josef Singer,Daniel M Mayer,Gudrun Pregartner,Annkristin Heine,Albert Wölfler,Heinz Sill,Andreas Reinisch,Armin Zebisch","doi":"10.1038/s41408-025-01396-5","DOIUrl":"https://doi.org/10.1038/s41408-025-01396-5","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"43 1","pages":"175"},"PeriodicalIF":12.8,"publicationDate":"2025-10-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145339337","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}
Pub Date : 2025-10-21DOI: 10.1038/s41408-025-01378-7
Dogan Yildiz,Ahmet Emre Eskazan
{"title":"STAMP inhibitors and their future in CML therapy: a critical analysis.","authors":"Dogan Yildiz,Ahmet Emre Eskazan","doi":"10.1038/s41408-025-01378-7","DOIUrl":"https://doi.org/10.1038/s41408-025-01378-7","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"15 1","pages":"173"},"PeriodicalIF":12.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338609","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}
Pub Date : 2025-10-21DOI: 10.1038/s41408-025-01369-8
Efstathios Kastritis, Panagiotis Malandrakis, Ioannis V Kostopoulos, Ioannis Ntanasis-Stathopoulos, Irene Solia, Foteini Theodorakakou, Vasiliki Spiliopoulou, Despina Fotiou, Magdalini Migkou, Nikolaos Kanellias, Evangelos Eleutherakis-Papaiakovou, Konstantina Taouxi, Alexandra Papadimou, Christine-Ivy Liacos, Maria Gavriatopoulou, Ourania Tsitsilonis, Evangelos Terpos, Meletios-Athanasios Dimopoulos
{"title":"Circulating tumor cells by Next Generation Flow Cytometry as a new prognostic biomarker for patients with asymptomatic monoclonal gammopathies.","authors":"Efstathios Kastritis, Panagiotis Malandrakis, Ioannis V Kostopoulos, Ioannis Ntanasis-Stathopoulos, Irene Solia, Foteini Theodorakakou, Vasiliki Spiliopoulou, Despina Fotiou, Magdalini Migkou, Nikolaos Kanellias, Evangelos Eleutherakis-Papaiakovou, Konstantina Taouxi, Alexandra Papadimou, Christine-Ivy Liacos, Maria Gavriatopoulou, Ourania Tsitsilonis, Evangelos Terpos, Meletios-Athanasios Dimopoulos","doi":"10.1038/s41408-025-01369-8","DOIUrl":"10.1038/s41408-025-01369-8","url":null,"abstract":"","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"15 1","pages":"170"},"PeriodicalIF":11.6,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12540748/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145343086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-21DOI: 10.1038/s41408-025-01373-y
Nicholas J Short,Elias Jabbour,Walid Macaron,Nitin Jain,Fadi G Haddad,Sanam Loghavi,Tapan M Kadia,Partow Kebriaei,Eitan Kugler,Jairo Matthews,Rebecca Garris,Farhad Ravandi,Hagop Kantarjian
Baseline cytomolecular features and measurable residual disease (MRD) dynamics are both strongly prognostic in acute lymphoblastic leukemia (ALL). Whether early MRD response can overcome the adverse prognosis of high-risk (HR) cytomolecular features is largely unknown. We retrospectively identified 161 patients with newly diagnosed B-cell ALL who underwent MRD assessment with next-generation sequencing (NGS) for IG/TR rearrangements (sensitivity: 1 × 10-6). Early NGS MRD negativity (i.e. after 1 cycle of induction) was achieved in 33% of patients. Rates of NGS MRD negativity were similar in patients with standard-risk (SR) and HR cytomolecular features. Patients who achieved early NGS MRD negativity had the best outcomes (2-year relapse-free survival (RFS): 94% versus 66% if MRD-positive; P = 0.03). None of the 26 patients with early NGS MRD negativity subsequently relapsed. Early NGS MRD response also identified patients with HR Philadelphia-chromosome (Ph)-negative ALL with low risk of relapse and excellent long-term survival (2-year RFS: 100%); in contrast, the 2-year RFS was 38% for patients with HR ALL who remained MRD-positive after induction (P = 0.01). Outcomes remained poor for HR patients who achieved NGS MRD negativity at later timepoints. In a landmark analysis, allogeneic stem cell transplant (alloSCT) improved outcomes of patients with HR Ph-negative ALL who remained MRD-positive after induction (2-year RFS 80% versus 0% if no alloSCT; P = 0.009). In patients with B-cell ALL, achievement of early NGS MRD negativity is associated with durable remissions, regardless of baseline cytomolecular features. AlloSCT may improve outcomes of patients with HR ALL with suboptimal early MRD dynamics.
{"title":"Prognostic impact of early NGS MRD dynamics and cytomolecular risk in newly diagnosed B-cell ALL.","authors":"Nicholas J Short,Elias Jabbour,Walid Macaron,Nitin Jain,Fadi G Haddad,Sanam Loghavi,Tapan M Kadia,Partow Kebriaei,Eitan Kugler,Jairo Matthews,Rebecca Garris,Farhad Ravandi,Hagop Kantarjian","doi":"10.1038/s41408-025-01373-y","DOIUrl":"https://doi.org/10.1038/s41408-025-01373-y","url":null,"abstract":"Baseline cytomolecular features and measurable residual disease (MRD) dynamics are both strongly prognostic in acute lymphoblastic leukemia (ALL). Whether early MRD response can overcome the adverse prognosis of high-risk (HR) cytomolecular features is largely unknown. We retrospectively identified 161 patients with newly diagnosed B-cell ALL who underwent MRD assessment with next-generation sequencing (NGS) for IG/TR rearrangements (sensitivity: 1 × 10-6). Early NGS MRD negativity (i.e. after 1 cycle of induction) was achieved in 33% of patients. Rates of NGS MRD negativity were similar in patients with standard-risk (SR) and HR cytomolecular features. Patients who achieved early NGS MRD negativity had the best outcomes (2-year relapse-free survival (RFS): 94% versus 66% if MRD-positive; P = 0.03). None of the 26 patients with early NGS MRD negativity subsequently relapsed. Early NGS MRD response also identified patients with HR Philadelphia-chromosome (Ph)-negative ALL with low risk of relapse and excellent long-term survival (2-year RFS: 100%); in contrast, the 2-year RFS was 38% for patients with HR ALL who remained MRD-positive after induction (P = 0.01). Outcomes remained poor for HR patients who achieved NGS MRD negativity at later timepoints. In a landmark analysis, allogeneic stem cell transplant (alloSCT) improved outcomes of patients with HR Ph-negative ALL who remained MRD-positive after induction (2-year RFS 80% versus 0% if no alloSCT; P = 0.009). In patients with B-cell ALL, achievement of early NGS MRD negativity is associated with durable remissions, regardless of baseline cytomolecular features. AlloSCT may improve outcomes of patients with HR ALL with suboptimal early MRD dynamics.","PeriodicalId":8989,"journal":{"name":"Blood Cancer Journal","volume":"12 1","pages":"169"},"PeriodicalIF":12.8,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145338610","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}
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