Blood Cancer Discovery最新文献_第6页

Bispecific Antibodies as Bridging to BCMA CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma. 双特异性抗体是治疗复发/难治性多发性骨髓瘤的 BCMA CAR-T 细胞疗法的桥梁。

IF 11.5

Blood Cancer Discovery Pub Date : 2025-01-08 DOI: 10.1158/2643-3230.BCD-24-0118

David Fandrei, Sabine Seiffert, Michael Rade, Susanne Rieprecht, Nico Gagelmann, Patrick Born, Thomas Wiemers, Heike Weidner, Markus Kreuz, Tamara Schassberger, Jannik Koßmann, Marlene Mangold, Daniel Fürst, Luise Fischer, Ronny Baber, Simone Heyn, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Köhl, Maik Friedrich, Andreas Boldt, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz

{"title":"Bispecific Antibodies as Bridging to BCMA CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma.","authors":"David Fandrei, Sabine Seiffert, Michael Rade, Susanne Rieprecht, Nico Gagelmann, Patrick Born, Thomas Wiemers, Heike Weidner, Markus Kreuz, Tamara Schassberger, Jannik Koßmann, Marlene Mangold, Daniel Fürst, Luise Fischer, Ronny Baber, Simone Heyn, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Köhl, Maik Friedrich, Andreas Boldt, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz","doi":"10.1158/2643-3230.BCD-24-0118","DOIUrl":"10.1158/2643-3230.BCD-24-0118","url":null,"abstract":"Establishing a strategy for sequencing of T cell-redirecting therapies for relapsed/refractory multiple myeloma (RRMM) is a pressing clinical need. We longitudinally tracked the clinical and immunologic impact of bispecific T cell-engaging antibodies (BsAb) as bridging therapy (BT) to subsequent B-cell maturation antigen-directed chimeric antigen receptor T (CAR-T) cell therapies in 52 patients with RRMM. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared with chemotherapy, anti-CD38, or anti-SLAMF7 antibody-based regimens (46%). We observed early CD4+CAR+ and delayed CD8+CAR+ T-cell expansion in patients receiving BsAbs as BT. In vitro cytotoxicity of CAR-T cells was comparable among BT options. Single-cell analyses revealed increased clonality in the CD4+ and CD8+ T-cell compartments in patients with previous exposure to BsAbs at leukapheresis and on day 30 after CAR-T cell infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM. Significance: CAR-T cell therapy and BsAbs have revolutionized treatment of triple-class refractory multiple myeloma; however, optimal sequencing is unknown. We demonstrate that BT with BsAb before B-cell maturation antigen-directed CAR-T cell therapy is safe and effective, which might have implications for other hematologic malignancies as well. See related commentary by Bal and Costa, p. 10.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"38-54"},"PeriodicalIF":11.5,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11707513/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142509384","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}

引用次数: 0

New Approvals Advancing Blood Cancer Medicine. 新批准推动血癌医学发展。

IF 11.5

Blood Cancer Discovery Pub Date : 2025-01-08 DOI: 10.1158/2643-3230.BCD-24-0300

引用次数: 0

Acknowledgment to Reviewers. 感谢审稿人。

IF 11.5

Blood Cancer Discovery Pub Date : 2025-01-08 DOI: 10.1158/2643-3230.BCD-6-1-AR

引用次数: 0

T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma: Optimal Dosing Schedule and Duration of Treatment. 治疗多发性骨髓瘤的 T 细胞重定向双特异性抗体：最佳用药方案和疗程。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-24-0124

Niels W C J van de Donk, Leo Rasche, Surbhi Sidana, Sonja Zweegman, Alfred L Garfall

{"title":"T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma: Optimal Dosing Schedule and Duration of Treatment.","authors":"Niels W C J van de Donk, Leo Rasche, Surbhi Sidana, Sonja Zweegman, Alfred L Garfall","doi":"10.1158/2643-3230.BCD-24-0124","DOIUrl":"10.1158/2643-3230.BCD-24-0124","url":null,"abstract":"T cell-redirecting bispecific antibodies (BsAb) induce significant responses in heavily pretreated multiple myeloma. BsAbs are currently administered in a dose-dense manner until disease progression. However, continuous therapy is associated with safety concerns, including a high risk of infections and high costs. In addition, chronic exposure to BsAbs, and thus long-term T-cell stimulation, induces T-cell exhaustion, which may contribute to relapse. There is increasing evidence that the strategy of induction treatment followed by maintenance with longer intervals between BsAb doses, or limited treatment duration with cessation of therapy in patients who achieve deep remission, improves the balance between toxicity and efficacy. Significance: There is increasing evidence that after initial debulking, less-frequent BsAb administration mitigates T-cell exhaustion and minimizes the potential for chronic or cumulative toxicity while maintaining durable clinical responses. In addition, specific patient subsets may experience an extended treatment-free period following fixed-duration treatment. Fixed-duration treatment may, therefore, decrease cumulative toxicities and the burden on patients and healthcare systems.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"388-399"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142355445","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}

引用次数: 0

Tracking Rare Single Donor and Recipient Immune and Leukemia Cells after Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations. 利用线粒体 DNA 突变追踪异体造血细胞移植后罕见的单个供体和受体免疫细胞和白血病细胞。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-23-0138

Livius Penter, Nicoletta Cieri, Katie Maurer, Marwan Kwok, Haoxiang Lyu, Wesley S Lu, Giacomo Oliveira, Satyen H Gohil, Ignaty Leshchiner, Caleb A Lareau, Leif S Ludwig, Donna S Neuberg, Haesook T Kim, Shuqiang Li, Lars Bullinger, Jerome Ritz, Gad Getz, Jacqueline S Garcia, Robert J Soiffer, Kenneth J Livak, Catherine J Wu

{"title":"Tracking Rare Single Donor and Recipient Immune and Leukemia Cells after Allogeneic Hematopoietic Cell Transplantation Using Mitochondrial DNA Mutations.","authors":"Livius Penter, Nicoletta Cieri, Katie Maurer, Marwan Kwok, Haoxiang Lyu, Wesley S Lu, Giacomo Oliveira, Satyen H Gohil, Ignaty Leshchiner, Caleb A Lareau, Leif S Ludwig, Donna S Neuberg, Haesook T Kim, Shuqiang Li, Lars Bullinger, Jerome Ritz, Gad Getz, Jacqueline S Garcia, Robert J Soiffer, Kenneth J Livak, Catherine J Wu","doi":"10.1158/2643-3230.BCD-23-0138","DOIUrl":"10.1158/2643-3230.BCD-23-0138","url":null,"abstract":"Combined tracking of clonal evolution and chimeric cell phenotypes could enable detection of the key cellular populations associated with response following therapy, including after allogeneic hematopoietic stem cell transplantation (HSCT). We demonstrate that mitochondrial DNA (mtDNA) mutations coevolve with somatic nuclear DNA mutations at relapse post-HSCT and provide a sensitive means to monitor these cellular populations. Furthermore, detection of mtDNA mutations via single-cell assay for transposase-accessible chromatin with select antigen profiling by sequencing (ASAP-seq) simultaneously determines not only donor and recipient cells but also their phenotype at frequencies of 0.1% to 1%. Finally, integration of mtDNA mutations, surface markers, and chromatin accessibility profiles enables the phenotypic resolution of leukemic populations from normal immune cells, thereby providing fresh insights into residual donor-derived engraftment and short-term clonal evolution following therapy for post-transplant leukemia relapse. As throughput evolves, we envision future development of single-cell sequencing-based post-transplant monitoring as a powerful approach for guiding clinical decision-making. Significance: mtDNA mutations enable single-cell tracking of leukemic clonal evolution and donor-recipient origin following allogeneic HSCT. This provides unprecedented insight into chimeric cellular phenotypes of early immune reconstitution, incipient relapse, and quality of donor engraftment with immediate translational potential for future clinical post-transplant monitoring and decision-making.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"442-459"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141274","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}

引用次数: 0

Repurposing NAMPT Inhibitors for Germinal Center B Cell-Like Diffuse Large B-Cell Lymphoma. 将 NAMPT 抑制剂重新用于治疗生殖中心 B 细胞样弥漫大 B 细胞淋巴瘤。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-24-0020

Claudio Scuoppo, Bowen Cai, Kenneth Ofori, Hanna Scholze, Rahul Kumar, Angelo D'Alessandro, Katia Basso, Laura Pasqualucci, Riccardo Dalla-Favera

{"title":"Repurposing NAMPT Inhibitors for Germinal Center B Cell-Like Diffuse Large B-Cell Lymphoma.","authors":"Claudio Scuoppo, Bowen Cai, Kenneth Ofori, Hanna Scholze, Rahul Kumar, Angelo D'Alessandro, Katia Basso, Laura Pasqualucci, Riccardo Dalla-Favera","doi":"10.1158/2643-3230.BCD-24-0020","DOIUrl":"10.1158/2643-3230.BCD-24-0020","url":null,"abstract":"Diffuse large B-cell lymphoma (DLBCL) includes the activated B cell-like (ABC) and germinal center B cell-like (GCB) subtypes, which differ in cell of origin, genetics, and clinical response. By screening the subtype-specific activity of 211 drugs approved or in active clinical development for other diseases, we identified inhibitors of nicotinamide phosphoribosyl transferase (NAMPTi) as active in a subset of GCB-DLBCL in vitro and in vivo. We validated three chemically distinct NAMPTis for their on-target activity based on biochemical and genetic rescue approaches and found the ratio between NAMPT and PARP1 RNA levels was predictive of NAMPTi sensitivity across DLBCL subtypes. Notably, the NAMPT:PARP1 transcript ratio predicts higher antitumor activity in BCL2-translocated GCB-DLBCL. Accordingly, pharmacologic and genetic inhibition of BCL2 was potently synergistic with NAMPT blockade. These data support the inhibition of NAMPT as a therapeutically relevant strategy for BCL2-translocated DLBCLs. Significance: Targeted therapies have emerged for the ABC subtype of DLBCL, but not for the GCB subtype, despite the evidence of a significant subset of high-risk cases. We identify a drug that specifically targets a subset of GCB-DLBCL and provide preclinical evidence for BCL2 translocations as biomarkers for their identification.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"417-427"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528193/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141894502","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}

引用次数: 0

A Role for Germline Variants in Multiple Myeloma? 种系变异在多发性骨髓瘤中的作用？

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-24-0226

Brian A Walker

引用次数: 0

A View of Myeloid Transformation through the Hallmarks of Cancer. 从癌症的标志看髓细胞转化。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-24-0009

Inés Fernández-Maestre, Sheng F Cai, Ross L Levine

{"title":"A View of Myeloid Transformation through the Hallmarks of Cancer.","authors":"Inés Fernández-Maestre, Sheng F Cai, Ross L Levine","doi":"10.1158/2643-3230.BCD-24-0009","DOIUrl":"10.1158/2643-3230.BCD-24-0009","url":null,"abstract":"The development of myeloid malignancies is influenced by a range of cell-intrinsic and cell-extrinsic factors, which can be conceptualized using the hallmarks of cancer. Although many facets of myeloid transformation are similar to those in solid tumors, there are also notable differences. Unlike solid tumors, hematologic malignancies typically exhibit fewer genetic mutations, which have been well characterized. However, understanding the cell-extrinsic factors contributing to myeloid malignancies can be challenging due to the complex interactions in the hematopoietic microenvironment. Researchers need to focus on these intricate factors to prevent the early onset of myeloid transformation and develop appropriate interventions. Significance: Myeloid malignancies are common in the elderly, and acute myeloid leukemia has an adverse prognosis in older patients. Investigating cell-extrinsic factors influencing myeloid malignancies is crucial to developing approaches for preventing or halting disease progression and predicting clinical outcomes in patients with advanced disease. Whereas successful intervention may require targeting various mechanisms, understanding the contribution of each cell-extrinsic factor will help prioritize clinical targets.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"377-387"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476402","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}

引用次数: 0

Multiple Myeloma Risk and Outcomes Are Associated with Pathogenic Germline Variants in DNA Repair Genes. 多发性骨髓瘤的风险和预后与 DNA 修复基因中的致病性基因变异有关。

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-23-0208

Santiago Thibaud, Ryan L Subaran, Scott Newman, Alessandro Lagana, David T Melnekoff, Saoirse Bodnar, Meghana Ram, Zachry Soens, William Genthe, Tehilla Brander, Tarek H Mouhieddine, Oliver Van Oekelen, Jane Houldsworth, Hearn Jay Cho, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Adriana Rossi, Larysa Sanchez, Ajai Chari, Erin Moshier, Sundar Jagannath, Samir Parekh, Kenan Onel

{"title":"Multiple Myeloma Risk and Outcomes Are Associated with Pathogenic Germline Variants in DNA Repair Genes.","authors":"Santiago Thibaud, Ryan L Subaran, Scott Newman, Alessandro Lagana, David T Melnekoff, Saoirse Bodnar, Meghana Ram, Zachry Soens, William Genthe, Tehilla Brander, Tarek H Mouhieddine, Oliver Van Oekelen, Jane Houldsworth, Hearn Jay Cho, Shambavi Richard, Joshua Richter, Cesar Rodriguez, Adriana Rossi, Larysa Sanchez, Ajai Chari, Erin Moshier, Sundar Jagannath, Samir Parekh, Kenan Onel","doi":"10.1158/2643-3230.BCD-23-0208","DOIUrl":"10.1158/2643-3230.BCD-23-0208","url":null,"abstract":"First-degree relatives of patients with multiple myeloma are at increased risk for the disease, but the contribution of pathogenic germline variants (PGV) in hereditary cancer genes to multiple myeloma risk and outcomes is not well characterized. To address this, we analyzed germline exomes in two independent cohorts of 895 and 786 patients with multiple myeloma. PGVs were identified in 8.6% of the Discovery cohort and 11.5% of the Replication cohort, with a notable presence of high- or moderate-penetrance PGVs (associated with autosomal dominant cancer predisposition) in DNA repair genes (3.6% and 4.1%, respectively). PGVs in BRCA1 (OR = 3.9, FDR < 0.01) and BRCA2 (OR = 7.0, FDR < 0.001) were significantly enriched in patients with multiple myeloma when compared with 134,187 healthy controls. Five of the eight BRCA2 PGV carriers exhibited tumor-specific copy number loss in BRCA2, suggesting somatic loss of heterozygosity. PGVs associated with autosomal dominant cancer predisposition were associated with younger age at diagnosis, personal or familial cancer history, and longer progression-free survival after upfront high-dose melphalan and autologous stem-cell transplantation (P < 0.01). Significance: Our findings suggest up to 10% of patients with multiple myeloma may have an unsuspected cancer predisposition syndrome. Given familial implications and favorable outcomes with high-dose melphalan and autologous stem-cell transplantation in high-penetrance PGV carriers, genetic testing should be considered for young or newly diagnosed patients with a personal or family cancer history. See related commentary by Walker, p. 375.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"428-441"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297062","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}

引用次数: 0

IF 11.5

Blood Cancer Discovery Pub Date : 2024-11-01 DOI: 10.1158/2643-3230.BCD-24-0103

Deepak Singhal, Monika M Kutyna, Christopher N Hahn, Mithun Vinod Shah, Devendra K Hiwase

{"title":"Therapy-Related Myeloid Neoplasms: Complex Interactions among Cytotoxic Therapies, Genetic Factors, and Aberrant Microenvironment.","authors":"Deepak Singhal, Monika M Kutyna, Christopher N Hahn, Mithun Vinod Shah, Devendra K Hiwase","doi":"10.1158/2643-3230.BCD-24-0103","DOIUrl":"10.1158/2643-3230.BCD-24-0103","url":null,"abstract":"Therapy-related myeloid neoplasm (t-MN), characterized by its association with prior exposure to cytotoxic therapy, remains poorly understood and is a major impediment to long-term survival even in the era of novel targeted therapies due to its aggressive nature and treatment resistance. Previously, cytotoxic therapy-induced genomic changes in hematopoietic stem cells were considered sine qua non in pathogenesis; however, recent research demonstrates a complex interaction between acquired and hereditary genetic predispositions, along with a profoundly senescent bone marrow (BM) microenvironment. We review emerging data on t-MN risk factors and explore the intricate interplay among clonal hematopoiesis, genetic predisposition, and the abnormal BM microenvironment. Significance: t-MN represents a poorly understood blood cancer with extremely poor survival and no effective therapies. We provide a comprehensive review of recent preclinical research highlighting complex interaction among emerging therapies, hereditary and acquired genetic factors, and BM microenvironment. Understanding the risk factors associated with t-MN is crucial for clinicians, molecular pathologists, and cancer biologists to anticipate and potentially reduce its incidence in the future. Moreover, better understanding of the molecular pathogenesis of t-MN may enable preemptive screening and even intervention in high-risk patients.","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"400-416"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142476403","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}

引用次数: 0