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":"<p><p>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.</p>","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}
{"title":"A Role for Germline Variants in Multiple Myeloma?","authors":"Brian A Walker","doi":"10.1158/2643-3230.BCD-24-0226","DOIUrl":"10.1158/2643-3230.BCD-24-0226","url":null,"abstract":"<p><p>In Blood Cancer Discovery, Thibaud and colleagues report the incidence of pathogenic germline variants (PGV) in patients with multiple myeloma and that these PGVs are associated with DNA repair pathway genes, including BRCA1 and BRCA2. They find an association of patients with PGVs and previous family or personal history of cancer, and that these patients are diagnosed slightly earlier than those without PGVs. Patients with PGVs had a longer progression-free survival than those without PGVs when they received high-dose melphalan and autologous stem cell transplant, providing a therapeutic rationale for diagnostic germline testing in myeloma. See related article by Thibaud et al., p. 428.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"375-376"},"PeriodicalIF":11.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528183/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142297061","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}
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":"<p><p>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.</p>","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}
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":"<p><p>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.</p>","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}
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 Furst, Luise Fischer, Ronny Baber, Simone Heyn, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herlling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Kohl, 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 Furst, Luise Fischer, Ronny Baber, Simone Heyn, Song Yau Wang, Enrica Bach, Sandra Hoffmann, Klaus H Metzeler, Marco Herlling, Madlen Jentzsch, Georg-Nikolaus Franke, Ulrike Kohl, Maik Friedrich, Andreas Boldt, Kristin Reiche, Uwe Platzbecker, Vladan Vucinic, Maximilian Merz","doi":"10.1158/2643-3230.BCD-24-0118","DOIUrl":"https://doi.org/10.1158/2643-3230.BCD-24-0118","url":null,"abstract":"<p><p>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 immunological impact of bispecific T cell engaging antibodies (BsAb) as bridging therapy (BT) to subsequent BCMA-directed CAR-T cell therapies in 52 RRMM patients. BsAbs were a potent and safe option for BT, achieving the highest overall response rate (100%) to BT compared to 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 BsAb as BT. In vitro cytotoxicity of CAR-T cells was comparable amongst 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 infusion. This study demonstrates the feasibility and efficacy of BT with BsAbs for CAR-T cell therapy in RRMM.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":11.5,"publicationDate":"2024-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142509384","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}
Martina Sarchi, Courtnee A Clough, Edie I Crosse, Jason Kim, Laura D Baquero Galvis, Nelli Aydinyan, Rachel Wellington, Feini Yang, Anna Gallì, J Philip Creamer, Sintra Stewart, Robert K Bradley, Luca Malcovati, Sergei Doulatov
{"title":"Mis-splicing of Mitotic Regulators Sensitizes SF3B1-Mutated Human HSCs to CHK1 Inhibition.","authors":"Martina Sarchi, Courtnee A Clough, Edie I Crosse, Jason Kim, Laura D Baquero Galvis, Nelli Aydinyan, Rachel Wellington, Feini Yang, Anna Gallì, J Philip Creamer, Sintra Stewart, Robert K Bradley, Luca Malcovati, Sergei Doulatov","doi":"10.1158/2643-3230.BCD-23-0230","DOIUrl":"10.1158/2643-3230.BCD-23-0230","url":null,"abstract":"<p><p>Splicing factor SF3B1 mutations are frequent somatic lesions in myeloid neoplasms that transform hematopoietic stem cells (HSCs) by inducing mis-splicing of target genes. However, the molecular and functional consequences of SF3B1 mutations in human HSCs and progenitors (HSPCs) remain unclear. Here, we identify the mis-splicing program in human HSPCs as a targetable vulnerability by precise gene editing of SF3B1 K700E mutations in primary CD34+ cells. Mutant SF3B1 induced pervasive mis-splicing and reduced expression of genes regulating mitosis and genome maintenance leading to altered differentiation, delayed G2/M progression, and profound sensitivity to CHK1 inhibition (CHK1i). Mis-splicing or reduced expression of mitotic regulators BUBR1 and CDC27 delayed G2/M transit and promoted CHK1i sensitivity. Clinical CHK1i prexasertib selectively targeted SF3B1-mutant immunophenotypic HSCs and abrogated engraftment in vivo. These findings identify mis-splicing of mitotic regulators in SF3B1-mutant HSPCs as a targetable vulnerability engaged by pharmacological CHK1 inhibition. Significance: In this study, we engineer precise SF3B1 mutations in human HSPCs and identify CHK1 inhibition as a selective vulnerability promoted by mis-splicing of mitotic regulators. These findings uncover the mis-splicing program induced by mutant SF3B1 in human HSPCs and show that it can be therapeutically targeted by clinical CHK1 inhibitors.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"353-370"},"PeriodicalIF":11.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369594/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141296892","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":"Oncogenic Enhancers in Leukemia.","authors":"Roger Mulet-Lazaro, Ruud Delwel","doi":"10.1158/2643-3230.BCD-23-0211","DOIUrl":"10.1158/2643-3230.BCD-23-0211","url":null,"abstract":"<p><p>Although the study of leukemogenesis has traditionally focused on protein-coding genes, the role of enhancer dysregulation is becoming increasingly recognized. The advent of high-throughput sequencing, together with a better understanding of enhancer biology, has revealed how various genetic and epigenetic lesions produce oncogenic enhancers that drive transformation. These aberrations include translocations that lead to enhancer hijacking, point mutations that modulate enhancer activity, and copy number alterations that modify enhancer dosage. In this review, we describe these mechanisms in the context of leukemia and discuss potential therapeutic avenues to target these regulatory elements. Significance: Large-scale sequencing projects have uncovered recurrent gene mutations in leukemia, but the picture remains incomplete: some patients harbor no such aberrations, whereas others carry only a few that are insufficient to bring about transformation on their own. One of the missing pieces is enhancer dysfunction, which only recently has emerged as a critical driver of leukemogenesis. Knowledge of the various mechanisms of enhancer dysregulation is thus key for a complete understanding of leukemia and its causes, as well as the development of targeted therapies in the era of precision medicine.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"303-317"},"PeriodicalIF":11.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369600/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876228","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}
Federico Stella, Annalisa Chiappella, Beatrice Casadei, Stefania Bramanti, Silva Ljevar, Patrizia Chiusolo, Alice Di Rocco, Maria C Tisi, Matteo G Carrabba, Ilaria Cutini, Massimo Martino, Anna Dodero, Francesca Bonifazi, Armando Santoro, Federica Sorà, Barbara Botto, Anna M Barbui, Domenico Russo, Maurizio Musso, Giovanni Grillo, Mauro Krampera, Jacopo Olivieri, Marco Ladetto, Federica Cavallo, Massimo Massaia, Luca Arcaini, Martina Pennisi, Pier L Zinzani, Rosalba Miceli, Paolo Corradini
{"title":"A Multicenter Real-life Prospective Study of Axicabtagene Ciloleucel versus Tisagenlecleucel Toxicity and Outcomes in Large B-cell Lymphomas.","authors":"Federico Stella, Annalisa Chiappella, Beatrice Casadei, Stefania Bramanti, Silva Ljevar, Patrizia Chiusolo, Alice Di Rocco, Maria C Tisi, Matteo G Carrabba, Ilaria Cutini, Massimo Martino, Anna Dodero, Francesca Bonifazi, Armando Santoro, Federica Sorà, Barbara Botto, Anna M Barbui, Domenico Russo, Maurizio Musso, Giovanni Grillo, Mauro Krampera, Jacopo Olivieri, Marco Ladetto, Federica Cavallo, Massimo Massaia, Luca Arcaini, Martina Pennisi, Pier L Zinzani, Rosalba Miceli, Paolo Corradini","doi":"10.1158/2643-3230.BCD-24-0052","DOIUrl":"10.1158/2643-3230.BCD-24-0052","url":null,"abstract":"<p><p>This real-world prospective observational study across 21 Italian centers (CART-SIE) compares axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) outcomes in 485 patients with relapsed/refractory large B-cell lymphoma with baseline characteristics matched by stabilized inverse propensity score weighting. Axi-cel versus tisa-cel had higher all-grade cytokine release syndrome (78.6% vs. 89.3%, P = 0.0017) and neurotoxicity (9.9% vs. 32.2%, P < 0.0001) but also superior progression-free survival (PFS) at 1 year (46.5% vs. 34.1%, P = 0.0009). Even among patients who failed bridging therapy, axi-cel PFS was superior to tisa-cel (37.5% vs. 22.7%, P = 0.0059). Differences in overall survival and high-grade immune toxicities were not significant. The CAR-HEMATOTOX score not only predicted hematologic toxicity but also 1-year survival outcomes (51.5% in CAR-HEMATOTOX high vs. 77.2% in CAR-HEMATOTOX low, P < 0.0001). Twenty patients developed second primary malignancies, including two cases of T-cell neoplasms. These findings enable more informed selection of anti-CD19 CAR T-cell therapy, balancing bridging, safety, and efficacy considerations for individual patients. Significance: The findings of this study on 485 patients with relapsed/refractory large B-cell lymphoma treated with commercial axi-cel and tisa-cel indicate axi-cel's superior PFS after propensity score weighting. The predictive utility of CAR-HEMATOTOX in assessing not only toxicity but also outcomes across both CAR T-cell products may guide future risk-stratified management strategies.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"318-330"},"PeriodicalIF":11.5,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11369587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141493710","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":"CAR T-cell Resistance to Oncogenic Transformation.","authors":"Marco Ruella, Carl H June","doi":"10.1158/2643-3230.BCD-23-0273","DOIUrl":"10.1158/2643-3230.BCD-23-0273","url":null,"abstract":"<p><p>In this commentary, we discuss the investigation into reports of T-cell malignancies following chimeric antigen receptor T-cell therapy. We argue that although these cases should be thoroughly examined, current data suggest that such risks with autologous chimeric antigen receptor T cells are remarkably low compared with other cancer treatments. We also emphasize the importance of continued research, transparent reporting, and participation in postauthorization safety studies.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"229-233"},"PeriodicalIF":11.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215395/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140877472","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}
Meir Rozenbaum, Reut Fluss, Victoria Marcu-Malina, Ifat Sarouk, Amilia Meir, Sarah Elitzur, Tal Zinger, Jasmine Jacob-Hirsch, Efrat G Saar, Gideon Rechavi, Elad Jacoby
{"title":"Genotoxicity Associated with Retroviral CAR Transduction of ATM-Deficient T Cells.","authors":"Meir Rozenbaum, Reut Fluss, Victoria Marcu-Malina, Ifat Sarouk, Amilia Meir, Sarah Elitzur, Tal Zinger, Jasmine Jacob-Hirsch, Efrat G Saar, Gideon Rechavi, Elad Jacoby","doi":"10.1158/2643-3230.BCD-23-0268","DOIUrl":"10.1158/2643-3230.BCD-23-0268","url":null,"abstract":"<p><p>Somatic variants in DNA damage response genes such as ATM are widespread in hematologic malignancies. ATM protein is essential for double-strand DNA break repair. Germline ATM deficiencies underlie ataxia-telangiectasia (A-T), a disease manifested by radiosensitivity, immunodeficiency, and predisposition to lymphoid malignancies. Patients with A-T diagnosed with malignancies have poor tolerance to chemotherapy or radiation. In this study, we investigated chimeric antigen receptor (CAR) T cells using primary T cells from patients with A-T (ATM-/-), heterozygote donors (ATM+/-), and healthy donors. ATM-/- T cells proliferate and can be successfully transduced with CARs, though functional impairment of ATM-/- CAR T-cells was observed. Retroviral transduction of the CAR in ATM-/- T cells resulted in high rates of chromosomal lesions at CAR insertion sites, as confirmed by next-generation long-read sequencing. This work suggests that ATM is essential to preserve genome integrity of CAR T-cells during retroviral manufacturing, and its lack poses a risk of chromosomal translocations and potential leukemogenicity. Significance: CAR T-cells are clinically approved genetically modified cells, but the control of genome integrity remains largely uncharacterized. This study demonstrates that ATM deficiency marginally impairs CAR T-cell function and results in high rates of chromosomal aberrations after retroviral transduction, which may be of concern in patients with DNA repair deficiencies.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":"267-275"},"PeriodicalIF":11.5,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215369/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140923531","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}