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101 results on '"Donna S. Neuberg"'

1. Venous thromboembolism in adolescents and young adults with acute lymphoblastic leukemia treated on a pediatric-inspired regimen

Author

Shai Shimony, Hari S. Raman, Yael Flamand, Julia Keating, Jonathan D. Paolino, Yannis K. Valtis, Andrew E. Place, Lewis B. Silverman, Stephen E. Sallan, Lynda M. Vrooman, Andrew M. Brunner, Donna S. Neuberg, Ilene Galinsky, Jacqueline S. Garcia, Eric S. Winer, Martha Wadleigh, Richard M. Stone, Jean M. Connors, Daniel J. DeAngelo, and Marlise R. Luskin

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Asparaginase (ASP)-containing regimens for acute lymphoblastic leukemia (ALL) are associated with venous thromboembolism (VTE). We evaluated the prevalence, risk factors, role of prophylaxis and clinical impact of VTE among adolescents and young adult (AYA) patients (15–50 years) treated on Dana-Farber Cancer Institute (DFCI) ALL protocols. The 1- and 2-year cumulative incidence of VTE were 31.9% (95% CI: 27.0%, 36.9%) and 33.5% (95% CI: 28.5%, 38.5%) respectively, with most events occurring during ASP-based consolidation phase (68.6%). VTE was more frequent in patients with overweight/obese vs. normal BMI (39.2% vs. 29.0%, p = 0.048). In a 1-year landmark analysis, the 4-year overall survival was 91.5%, without difference between patients with vs. without VTE (93.8% vs. 90.0%, p = 0.93). Relapse and non-relapse mortality rates were also similar. Among patients treated at Dana-Farber/Harvard Cancer Center, cerebral sinus vein thrombosis occurred in 3.6% of patients (8.5% of VTE events) in comparison to pulmonary embolism (32.9%) and deep vein thromboses (58.6%, 24.4% line-associated). In a Cox regression model for VTE free-time, elevated BMI was associated with shorter VTE free-time (HR 1.94 [95% CI 1.13-3.35], p = 0.018), while low molecular weight heparin (LMWH) prophylaxis as time-varying covariate was not. In conclusion, we found that VTE was frequent in AYAs treated on DFCI ALL protocols but did not impact survival outcomes. Overweight/obese BMI increased risk for VTE.

Published
2024
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2. A stapled lipopeptide platform for preventing and treating highly pathogenic viruses of pandemic potential

Author

Gregory H. Bird, J. J. Patten, William Zavadoski, Nicole Barucci, Marina Godes, Benjamin M. Moyer, Callum D. Owen, Paul DaSilva-Jardine, Donna S. Neuberg, Richard A. Bowen, Robert A. Davey, and Loren D. Walensky

Subjects
Science
Abstract

Abstract The continued emergence of highly pathogenic viruses, which either thwart immune- and small molecule-based therapies or lack interventions entirely, mandates alternative approaches, particularly for prompt and facile pre- and post-exposure prophylaxis. Many highly pathogenic viruses, including coronaviruses, employ the six-helix bundle heptad repeat membrane fusion mechanism to achieve infection. Although heptad-repeat-2 decoys can inhibit viral entry by blocking six-helix bundle assembly, the biophysical and pharmacologic liabilities of peptides have hindered their clinical development. Here, we develop a chemically stapled lipopeptide inhibitor of SARS-CoV-2 as proof-of-concept for the platform. We show that our lead compound blocks infection by a spectrum of SARS-CoV-2 variants, exhibits mucosal persistence upon nasal administration, demonstrates enhanced stability compared to prior analogs, and mitigates infection in hamsters. We further demonstrate that our stapled lipopeptide platform yields nanomolar inhibitors of respiratory syncytial, Ebola, and Nipah viruses by targeting heptad-repeat-1 domains, which exhibit strikingly low mutation rates, enabling on-demand therapeutic intervention to combat viral outbreaks.

Published
2024
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3. Integrative genotyping of cancer and immune phenotypes by long-read sequencing

Author

Livius Penter, Mehdi Borji, Adi Nagler, Haoxiang Lyu, Wesley S. Lu, Nicoletta Cieri, Katie Maurer, Giacomo Oliveira, Aziz M. Al’Khafaji, Kiran V. Garimella, Shuqiang Li, Donna S. Neuberg, Jerome Ritz, Robert J. Soiffer, Jacqueline S. Garcia, Kenneth J. Livak, and Catherine J. Wu

Subjects
Science
Abstract

Abstract Single-cell transcriptomics has become the definitive method for classifying cell types and states, and can be augmented with genotype information to improve cell lineage identification. Due to constraints of short-read sequencing, current methods to detect natural genetic barcodes often require cumbersome primer panels and early commitment to targets. Here we devise a flexible long-read sequencing workflow and analysis pipeline, termed nanoranger, that starts from intermediate single-cell cDNA libraries to detect cell lineage-defining features, including single-nucleotide variants, fusion genes, isoforms, sequences of chimeric antigen and TCRs. Through systematic analysis of these classes of natural ‘barcodes’, we define the optimal targets for nanoranger, namely those loci close to the 5’ end of highly expressed genes with transcript lengths shorter than 4 kB. As proof-of-concept, we apply nanoranger to longitudinal tracking of subclones of acute myeloid leukemia (AML) and describe the heterogeneous isoform landscape of thousands of marrow-infiltrating immune cells. We propose that enhanced cellular genotyping using nanoranger can improve the tracking of single-cell tumor and immune cell co-evolution.

Published
2024
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4. Mapping the evolution of T cell states during response and resistance to adoptive cellular therapy

Author

Pavan Bachireddy, Elham Azizi, Cassandra Burdziak, Vinhkhang N. Nguyen, Christina S. Ennis, Katie Maurer, Cameron Y. Park, Zi-Ning Choo, Shuqiang Li, Satyen H. Gohil, Neil G. Ruthen, Zhongqi Ge, Derin B. Keskin, Nicoletta Cieri, Kenneth J. Livak, Haesook T. Kim, Donna S. Neuberg, Robert J. Soiffer, Jerome Ritz, Edwin P. Alyea, Dana Pe’er, and Catherine J. Wu

Subjects
Biology (General), QH301-705.5
Published
2023
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5. Mechanisms of response and resistance to combined decitabine and ipilimumab for advanced myeloid disease

Author

Livius Penter, Yang Liu, Jacquelyn O. Wolff, Lin Yang, Len Taing, Aashna Jhaveri, Jackson Southard, Manishkumar Patel, Nicole M. Cullen, Kathleen L. Pfaff, Nicoletta Cieri, Giacomo Oliveira, Seunghee Kim-Schulze, Srinika Ranasinghe, Rebecca Leonard, Taylor Robertson, Elizabeth A. Morgan, Helen X. Chen, Minkyung H. Song, Magdalena Thurin, Shuqiang Li, Scott J. Rodig, Carrie Cibulskis, Stacey Gabriel, Pavan Bachireddy, Jerome Ritz, Howard Streicher, Donna S. Neuberg, F. Stephen Hodi, Matthew S. Davids, Sacha Gnjatic, Kenneth J. Livak, Jennifer Altreuter, Franziska Michor, Robert J. Soiffer, Jacqueline S. Garcia, and Catherine J. Wu

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

The challenge of eradicating leukemia in patients with acute myelogenous leukemia (AML) after initial cytoreduction has motivated modern efforts to combine synergistic active modalities including immunotherapy. Recently, the ETCTN/CTEP 10026 study tested the combination of the DNA methyltransferase inhibitor decitabine together with the immune checkpoint inhibitor ipilimumab for AML/myelodysplastic syndrome (MDS) either after allogeneic hematopoietic stem cell transplantation (HSCT) or in the HSCT-naïve setting. Integrative transcriptome-based analysis of 304 961 individual marrow-infiltrating cells for 18 of 48 subjects treated on study revealed the strong association of response with a high baseline ratio of T to AML cells. Clinical responses were predominantly driven by decitabine-induced cytoreduction. Evidence of immune activation was only apparent after ipilimumab exposure, which altered CD4+ T-cell gene expression, in line with ongoing T-cell differentiation and increased frequency of marrow-infiltrating regulatory T cells. For post-HSCT samples, relapse could be attributed to insufficient clearing of malignant clones in progenitor cell populations. In contrast to AML/MDS bone marrow, the transcriptomes of leukemia cutis samples from patients with durable remission after ipilimumab monotherapy showed evidence of increased infiltration with antigen-experienced resident memory T cells and higher expression of CTLA-4 and FOXP3. Altogether, activity of combined decitabine and ipilimumab is impacted by cellular expression states within the microenvironmental niche of leukemic cells. The inadequate elimination of leukemic progenitors mandates urgent development of novel approaches for targeting these cell populations to generate long-lasting responses. This trial was registered at www.clinicaltrials.gov as #NCT02890329.

Published
2023

6. Nelarabine combination therapy for relapsed or refractory T-cell acute lymphoblastic lymphoma/leukemia

Author

Shai Shimony, Yiwen Liu, Yannis K. Valtis, Jonathan D. Paolino, Andrew E. Place, Andrew M. Brunner, Lachelle D. Weeks, Lewis B. Silverman, Lynda M. Vrooman, Donna S. Neuberg, Richard M. Stone, Daniel J. DeAngelo, and Marlise R. Luskin

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Nelarabine, an antimetabolite prodrug, is approved as monotherapy for children and adults with relapsed and refractory T-cell acute lymphoblastic leukemia and lymphoma (R/R T-ALL/LBL), although it is often used in combination regimens. We sought to understand differences in efficacy and toxicity when nelarabine is administered alone or in combination. We retrospectively analyzed 44 consecutive patients with R/R T-ALL/LBL; 29 of whom were treated with combination therapy, most with cyclophosphamide and etoposide (23, 79%) and 15 with monotherapy. The median age was 19 years (range, 2-69), including 18 children (

Published
2023

7. In VivoModeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Author

Elisa ten Hacken, Tomasz Sewastianik, Shanye Yin, Gabriela Brunsting Hoffmann, Michaela Gruber, Kendell Clement, Livius Penter, Robert A. Redd, Neil Ruthen, Sébastien Hergalant, Alanna Sholokhova, Geoffrey Fell, Erin M. Parry, Julien Broséus, Romain Guieze, Fabienne Lucas, María Hernández-Sánchez, Kaitlyn Baranowski, Jackson Southard, Heather Joyal, Leah Billington, Fara Faye D. Regis, Elizabeth Witten, Mohamed Uduman, Binyamin A. Knisbacher, Shuqiang Li, Haoxiang Lyu, Tiziana Vaisitti, Silvia Deaglio, Giorgio Inghirami, Pierre Feugier, Stephan Stilgenbauer, Eugen Tausch, Matthew S. Davids, Gad Getz, Kenneth J. Livak, Ivana Bozic, Donna S. Neuberg, Ruben D. Carrasco, and Catherine J. Wu

Subjects
General Medicine
Abstract

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.Significance:Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease.This article is highlighted in the In This Issue feature, p. 101

Published
2022

8. Evolutionary History of Transformation from Chronic Lymphocytic Leukemia to Richter Syndrome

Author

Erin Michelle Parry, Romain Guieze, Ignaty Leshchiner, Connor Johnson, Eugen Tausch, Sameer A. Parikh, Camilla K Lemvigh, Julien Broséus, Sébastien Hergalant, Connor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Liang Li, Shuqiang Li, Geoffrey G Fell, Robert A. Redd, Ziao Lin, Binyamin A. Knisbacher, Christof Schneider, Stacey M. Fernandes, Julian M. Hess, Laura Z. Rassenti, Thomas J. Kipps, Nitin Jain, William G. Wierda, Florence Cymbalista, Pierre Feugier, Neil E. Kay, Kenneth J Livak, Brian P Danysh, Chip Stewart, Donna S. Neuberg, Matthew S. Davids, Jennifer R. Brown, Laxmi Parida, Stephan Stilgenbauer, Gad Getz, and Catherine J. Wu

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022

11. Figure S5 from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy

Author

Alexander Meissner, Catherine J. Wu, Andreas Gnirke, Elias Campo, Thomas J. Kipps, Bernd Timmermann, Sven Klages, Donna S. Neuberg, Kenneth J. Livak, Shuqiang Li, Lili Wang, Jennifer R. Brown, Stacey M. Fernandes, Neil E. Kay, Tait D. Shanafelt, Esteban Braggio, Susan L. Slager, Connie Lesnick, Arman W. Mohammad, Laura Rassenti, Hongcang Gu, Michaela Gruber, Kendell Clement, Camilla K. Lemvigh, Noelia Purroy, Anat Biran, and Helene Kretzmer

Abstract

Non-uniform dynamics of single CpGs among CLL progression

Published
2023

12. Data from In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Author

Catherine J. Wu, Ruben D. Carrasco, Donna S. Neuberg, Ivana Bozic, Kenneth J. Livak, Gad Getz, Matthew S. Davids, Eugen Tausch, Stephan Stilgenbauer, Pierre Feugier, Giorgio Inghirami, Silvia Deaglio, Tiziana Vaisitti, Haoxiang Lyu, Shuqiang Li, Binyamin A. Knisbacher, Mohamed Uduman, Elizabeth Witten, Fara Faye D. Regis, Leah Billington, Heather Joyal, Jackson Southard, Kaitlyn Baranowski, María Hernández-Sánchez, Fabienne Lucas, Romain Guieze, Julien Broséus, Erin M. Parry, Geoffrey Fell, Alanna Sholokhova, Sébastien Hergalant, Neil Ruthen, Robert A. Redd, Livius Penter, Kendell Clement, Michaela Gruber, Gabriela Brunsting Hoffmann, Shanye Yin, Tomasz Sewastianik, and Elisa ten Hacken

Abstract

Transformation to aggressive disease histologies generates formidable clinical challenges across cancers, but biological insights remain few. We modeled the genetic heterogeneity of chronic lymphocytic leukemia (CLL) through multiplexed in vivo CRISPR-Cas9 B-cell editing of recurrent CLL loss-of-function drivers in mice and recapitulated the process of transformation from indolent CLL into large cell lymphoma [i.e., Richter syndrome (RS)]. Evolutionary trajectories of 64 mice carrying diverse combinatorial gene assortments revealed coselection of mutations in Trp53, Mga, and Chd2 and the dual impact of clonal Mga/Chd2 mutations on E2F/MYC and interferon signaling dysregulation. Comparative human and murine RS analyses demonstrated tonic PI3K signaling as a key feature of transformed disease, with constitutive activation of the AKT and S6 kinases, downmodulation of the PTEN phosphatase, and convergent activation of MYC/PI3K transcriptional programs underlying enhanced sensitivity to MYC/mTOR/PI3K inhibition. This robust experimental system presents a unique framework to study lymphoid biology and therapy.Significance:Mouse models reflective of the genetic complexity and heterogeneity of human tumors remain few, including those able to recapitulate transformation to aggressive disease histologies. Herein, we model CLL transformation into RS through multiplexed in vivo gene editing, providing key insight into the pathophysiology and therapeutic vulnerabilities of transformed disease.This article is highlighted in the In This Issue feature, p. 101

Published
2023

13. Supplementary Figures from In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Author

Catherine J. Wu, Ruben D. Carrasco, Donna S. Neuberg, Ivana Bozic, Kenneth J. Livak, Gad Getz, Matthew S. Davids, Eugen Tausch, Stephan Stilgenbauer, Pierre Feugier, Giorgio Inghirami, Silvia Deaglio, Tiziana Vaisitti, Haoxiang Lyu, Shuqiang Li, Binyamin A. Knisbacher, Mohamed Uduman, Elizabeth Witten, Fara Faye D. Regis, Leah Billington, Heather Joyal, Jackson Southard, Kaitlyn Baranowski, María Hernández-Sánchez, Fabienne Lucas, Romain Guieze, Julien Broséus, Erin M. Parry, Geoffrey Fell, Alanna Sholokhova, Sébastien Hergalant, Neil Ruthen, Robert A. Redd, Livius Penter, Kendell Clement, Michaela Gruber, Gabriela Brunsting Hoffmann, Shanye Yin, Tomasz Sewastianik, and Elisa ten Hacken

Abstract

Supplementary file contains a PDF version of supplementary figures S1-S7 and associated figure legends.

Published
2023

14. Table S3 from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy

Author

Alexander Meissner, Catherine J. Wu, Andreas Gnirke, Elias Campo, Thomas J. Kipps, Bernd Timmermann, Sven Klages, Donna S. Neuberg, Kenneth J. Livak, Shuqiang Li, Lili Wang, Jennifer R. Brown, Stacey M. Fernandes, Neil E. Kay, Tait D. Shanafelt, Esteban Braggio, Susan L. Slager, Connie Lesnick, Arman W. Mohammad, Laura Rassenti, Hongcang Gu, Michaela Gruber, Kendell Clement, Camilla K. Lemvigh, Noelia Purroy, Anat Biran, and Helene Kretzmer

Abstract

Table of correlation between time points within one sample and number of hyper- or hypomethylated CpGs for all CLL (top) and naïve and memory B cell samples (bottom)

Published
2023

15. Supplementary Tables from In Vivo Modeling of CLL Transformation to Richter Syndrome Reveals Convergent Evolutionary Paths and Therapeutic Vulnerabilities

Author

Catherine J. Wu, Ruben D. Carrasco, Donna S. Neuberg, Ivana Bozic, Kenneth J. Livak, Gad Getz, Matthew S. Davids, Eugen Tausch, Stephan Stilgenbauer, Pierre Feugier, Giorgio Inghirami, Silvia Deaglio, Tiziana Vaisitti, Haoxiang Lyu, Shuqiang Li, Binyamin A. Knisbacher, Mohamed Uduman, Elizabeth Witten, Fara Faye D. Regis, Leah Billington, Heather Joyal, Jackson Southard, Kaitlyn Baranowski, María Hernández-Sánchez, Fabienne Lucas, Romain Guieze, Julien Broséus, Erin M. Parry, Geoffrey Fell, Alanna Sholokhova, Sébastien Hergalant, Neil Ruthen, Robert A. Redd, Livius Penter, Kendell Clement, Michaela Gruber, Gabriela Brunsting Hoffmann, Shanye Yin, Tomasz Sewastianik, and Elisa ten Hacken

Abstract

Supplementary file contains all supplementary tables S1-S16 in Excel format in the order in which they appear in the text.

Published
2023

16. Supplementary Tables S1-S19 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author

Benjamin L. Ebert, Siddhartha Jaiswal, Robert K. Bradley, Gad Getz, Chip Stewart, Elli Papaemmanuil, Luca Malcovati, Eva Hellstrom-Lindberg, Steven A. Carr, Kasper Lage, Donna S. Neuberg, Monkol Lek, Daniel G. MacArthur, Ruth Loos, Andrew D. Johnson, Michael H. Cho, Pinkal Desai, Bruce M. Psaty, Shankara Anand, Alex Barbera, Timothy Wood, Amaro Taylor-Weiner, Andrew Dunford, Abhishek Niroula, Mendy Miller, Joshua S. Weinstock, Alexander G. Bick, Björn Nilsson, Edyta Malolepsza, Benjamin Tanenbaum, Caroline Stanclift, Monica Schenone, Waihay Wong, Akansha Tarun, Marie McConkey, Cecilia A. Castellano, Anna Gallì, Maria Creignou, Gabriele Todisco, Emma R. Hoppe, Elsa Bernard, Matthew Leventhal, and Ellen M. Beauchamp

Abstract

Supplementary Tables S1-S19

Published
2023

17. Data from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author

Benjamin L. Ebert, Siddhartha Jaiswal, Robert K. Bradley, Gad Getz, Chip Stewart, Elli Papaemmanuil, Luca Malcovati, Eva Hellstrom-Lindberg, Steven A. Carr, Kasper Lage, Donna S. Neuberg, Monkol Lek, Daniel G. MacArthur, Ruth Loos, Andrew D. Johnson, Michael H. Cho, Pinkal Desai, Bruce M. Psaty, Shankara Anand, Alex Barbera, Timothy Wood, Amaro Taylor-Weiner, Andrew Dunford, Abhishek Niroula, Mendy Miller, Joshua S. Weinstock, Alexander G. Bick, Björn Nilsson, Edyta Malolepsza, Benjamin Tanenbaum, Caroline Stanclift, Monica Schenone, Waihay Wong, Akansha Tarun, Marie McConkey, Cecilia A. Castellano, Anna Gallì, Maria Creignou, Gabriele Todisco, Emma R. Hoppe, Elsa Bernard, Matthew Leventhal, and Ellen M. Beauchamp

Abstract

Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader ZBTB33 as well as in YLPM1, SRCAP, and ZNF318. We also identified these mutations at low frequency in patients with myelodysplastic syndrome. Zbtb33-edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage in vivo and increased genome-wide intron retention. ZBTB33 mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and myelodysplastic syndromes.Significance:Mutations in known driver genes can be found in only about half of individuals with clonal hematopoiesis. Here, we performed a somatic mutation discovery effort in nonmalignant blood samples, which identified novel candidate genes that may play biological roles in hematopoietic stem cell expansion and hematologic malignancies.This article is highlighted in the In This Issue feature, p. 403

Published
2023

18. Supplementary Figures and Legends from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy

Author

Alexander Meissner, Catherine J. Wu, Andreas Gnirke, Elias Campo, Thomas J. Kipps, Bernd Timmermann, Sven Klages, Donna S. Neuberg, Kenneth J. Livak, Shuqiang Li, Lili Wang, Jennifer R. Brown, Stacey M. Fernandes, Neil E. Kay, Tait D. Shanafelt, Esteban Braggio, Susan L. Slager, Connie Lesnick, Arman W. Mohammad, Laura Rassenti, Hongcang Gu, Michaela Gruber, Kendell Clement, Camilla K. Lemvigh, Noelia Purroy, Anat Biran, and Helene Kretzmer

Abstract

Supplementary Figures 1-7 and matching legends

Published
2023

19. Supplementary Figures S1-S11 from ZBTB33 Is Mutated in Clonal Hematopoiesis and Myelodysplastic Syndromes and Impacts RNA Splicing

Author

Benjamin L. Ebert, Siddhartha Jaiswal, Robert K. Bradley, Gad Getz, Chip Stewart, Elli Papaemmanuil, Luca Malcovati, Eva Hellstrom-Lindberg, Steven A. Carr, Kasper Lage, Donna S. Neuberg, Monkol Lek, Daniel G. MacArthur, Ruth Loos, Andrew D. Johnson, Michael H. Cho, Pinkal Desai, Bruce M. Psaty, Shankara Anand, Alex Barbera, Timothy Wood, Amaro Taylor-Weiner, Andrew Dunford, Abhishek Niroula, Mendy Miller, Joshua S. Weinstock, Alexander G. Bick, Björn Nilsson, Edyta Malolepsza, Benjamin Tanenbaum, Caroline Stanclift, Monica Schenone, Waihay Wong, Akansha Tarun, Marie McConkey, Cecilia A. Castellano, Anna Gallì, Maria Creignou, Gabriele Todisco, Emma R. Hoppe, Elsa Bernard, Matthew Leventhal, and Ellen M. Beauchamp

Abstract

Supplementary Figures S1-S11

Published
2023

20. Data from Preneoplastic Alterations Define CLL DNA Methylome and Persist through Disease Progression and Therapy

Author

Alexander Meissner, Catherine J. Wu, Andreas Gnirke, Elias Campo, Thomas J. Kipps, Bernd Timmermann, Sven Klages, Donna S. Neuberg, Kenneth J. Livak, Shuqiang Li, Lili Wang, Jennifer R. Brown, Stacey M. Fernandes, Neil E. Kay, Tait D. Shanafelt, Esteban Braggio, Susan L. Slager, Connie Lesnick, Arman W. Mohammad, Laura Rassenti, Hongcang Gu, Michaela Gruber, Kendell Clement, Camilla K. Lemvigh, Noelia Purroy, Anat Biran, and Helene Kretzmer

Abstract

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset.Significance:DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism.See related commentary by Rossi, p. 6.This article is highlighted in the In This Issue feature, p. 1

Published
2023

21. Supplementary Table 8 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 24K, PCR Primer sequences.

Published
2023

22. Supplementary methods from Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status

Author

Scott J. Rodig, Margaret A. Shipp, Donna S. Neuberg, Richard T. Hoppe, Daphne de Jong, Bjoern Chapuy, Sarah E. Daadi, Christopher D. Carey, Christine J. Pak, Courtney F. Connelly, Azra H. Ligon, Yasodha Natkunam, Geraldine S. Pinkus, Robert A. Redd, Ranjana H. Advani, and Margaretha G.M. Roemer

Abstract

Supplementary methods

Published
2023

23. Data from Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status

Author

Scott J. Rodig, Margaret A. Shipp, Donna S. Neuberg, Richard T. Hoppe, Daphne de Jong, Bjoern Chapuy, Sarah E. Daadi, Christopher D. Carey, Christine J. Pak, Courtney F. Connelly, Azra H. Ligon, Yasodha Natkunam, Geraldine S. Pinkus, Robert A. Redd, Ranjana H. Advani, and Margaretha G.M. Roemer

Abstract

In classical Hodgkin lymphoma (cHL), malignant Hodgkin Reed–Sternberg (HRS) cells evade antitumor immunity by multiple mechanisms, including perturbed antigen presentation and enhanced PD-1 signaling. HRS cell expression of the PD-1 ligands is attributable, in part, to copy number alterations of 9p24.1/CD274(PD-L1)/PDCD1LG2(PD-L2). Amplification of PD-L1/PD-L2 is associated with advanced clinical stage and inferior progression-free survival (PFS) following first-line (induction) therapy. The relationships between altered expression of β2-microglobulin (β2M), MHC class I, and MHC class II by HRS cells, PD-L1/PD-L2 amplification, and clinical outcome in cHL are poorly defined. We assessed these variables in diagnostic biopsy specimens from 108 patients with cHL who received uniform treatment and had long-term follow-up and found decreased/absent expression of β2M/MHC class I in 79% (85/108) and decreased/absent expression of MHC class II in 67% (72/108) of cases. Patients with decreased/absent β2M/MHC class I had shorter PFS, independent of PD-L1/PD-L2 amplification and advanced stage. Decreased or absent MHC class II was unrelated to outcome. These results suggest that MHC class I–mediated antigen presentation by HRS cells is an important component of the biological response to standard chemo/radiotherapy. The paucity of β2M/MHC class I expression on HRS cells also prompts speculation regarding alternative mechanisms of action of PD-1 blockade in cHL. Cancer Immunol Res; 4(11); 910–6. ©2016 AACR.

Published
2023

24. Supplementary Figure 9 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 113K, Bcl2 protein expression in wild-type and Tyk2 knockout mice.

Published
2023

25. Table S3 from Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma

Author

Sarah Nikiforow, Jerome Ritz, Glenn Dranoff, Robert Soiffer, Donna S. Neuberg, Richard M. Stone, Nikhil C. Munshi, Kristen Cummings, Heidi DiPietro, Ilene Galinsky, Frédéric F. Lehmann, David E. Gilham, Charles L. Sentman, Jake Reder, Adam Schmucker, Joanina K. Gicobi, Helene Trebeden-Negre, Heather Daley, Lillian Werner, Joana Murad, and Susanne H. Baumeister

Abstract

Adverse Events

Published
2023

26. Supplementary Figure 4 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 74K, Knockdown efficiency and BCL2 expression in JURKAT cells.

Published
2023

27. Supplementary Table 2 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 525K, Summary of inducible shRNA screen on three T-ALL cell lines.

Published
2023

28. Supplementary Data from Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History

Author

Catherine J. Wu, Vijay G. Sankaran, Kenneth J. Livak, Donna S. Neuberg, Matthew S. Davids, Jennifer R. Brown, Thomas J. Kipps, Laura Z. Rassenti, Gad Getz, Laxmi Parida, Ignaty Leshchiner, Dimitri Livitz, Wandi Zhang, Shuqiang Li, Teddy Huang, Erin M. Parry, Leif S. Ludwig, Caleb Lareau, Satyen H. Gohil, and Livius Penter

Abstract

Supplementary methods, Table S1, supplementary figures 1-9

Published
2023

29. Supplementary Table 1 from Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status

Author

Scott J. Rodig, Margaret A. Shipp, Donna S. Neuberg, Richard T. Hoppe, Daphne de Jong, Bjoern Chapuy, Sarah E. Daadi, Christopher D. Carey, Christine J. Pak, Courtney F. Connelly, Azra H. Ligon, Yasodha Natkunam, Geraldine S. Pinkus, Robert A. Redd, Ranjana H. Advani, and Margaretha G.M. Roemer

Abstract

Percent exact agreement and weighted Cohen's kappa coefficient with bootstrap 95% confidence intervals.

Published
2023

30. Supplementary Figure Legend and Methods from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 138K

Published
2023

31. Data from Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History

Author

Catherine J. Wu, Vijay G. Sankaran, Kenneth J. Livak, Donna S. Neuberg, Matthew S. Davids, Jennifer R. Brown, Thomas J. Kipps, Laura Z. Rassenti, Gad Getz, Laxmi Parida, Ignaty Leshchiner, Dimitri Livitz, Wandi Zhang, Shuqiang Li, Teddy Huang, Erin M. Parry, Leif S. Ludwig, Caleb Lareau, Satyen H. Gohil, and Livius Penter

Abstract

While cancers evolve during disease progression and in response to therapy, temporal dynamics remain difficult to study in humans due to the lack of consistent barcodes marking individual clones in vivo. We employ mitochondrial single-cell assay for transposase-accessible chromatin with sequencing to profile 163,279 cells from 9 patients with chronic lymphocytic leukemia (CLL) collected across disease course and utilize mitochondrial DNA (mtDNA) mutations as natural genetic markers of cancer clones. We observe stable propagation of mtDNA mutations over years in the absence of strong selective pressure, indicating clonal persistence, but dramatic changes following tight bottlenecks, including disease transformation and relapse posttherapy, paralleled by acquisition of copy-number variants and changes in chromatin accessibility and gene expression. Furthermore, we link CLL subclones to distinct chromatin states, providing insight into nongenetic sources of relapse. mtDNA mutations thus mirror disease history and provide naturally occurring genetic barcodes to enable patient-specific study of cancer subclonal dynamics.Significance:Single-cell multi-omic profiling of CLL reveals the utility of somatic mtDNA mutations as in vivo barcodes, which mark subclones that can evolve over time along with changes in accessible chromatin and gene expression profiles to capture dynamics of disease evolution.See related commentary by Hilton and Scott, p. 2965.This article is highlighted in the In This Issue feature, p. 2945

Published
2023

32. Supplementary Figure 6 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 32K, Expressions of IL-10 and IL-10 receptors, and effect of an anti-IL10 neutralizing antibody on growth of T-ALL cell lines.

Published
2023

33. Supplementary Table 3 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 30K, Targeting sequences for shRNAs.

Published
2023

34. Table S2 from Longitudinal Single-Cell Dynamics of Chromatin Accessibility and Mitochondrial Mutations in Chronic Lymphocytic Leukemia Mirror Disease History

Author

Catherine J. Wu, Vijay G. Sankaran, Kenneth J. Livak, Donna S. Neuberg, Matthew S. Davids, Jennifer R. Brown, Thomas J. Kipps, Laura Z. Rassenti, Gad Getz, Laxmi Parida, Ignaty Leshchiner, Dimitri Livitz, Wandi Zhang, Shuqiang Li, Teddy Huang, Erin M. Parry, Leif S. Ludwig, Caleb Lareau, Satyen H. Gohil, and Livius Penter

Abstract

Supplementary Table 2 - %CLL cells marked by mtDNA mutations

Published
2023

35. Supplementary Figure 2 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 68K, Cell cycle distribution after TYK2 knockdown in T-ALL cells.

Published
2023

36. Supplementary Table 5 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 14291K, TYK2 genotype in 17 T-ALL cell lines.

Published
2023

37. Supplementary Table 4 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 35K, Sensitivities to TYK2 knockdown and JAK Inhibitor I treatment, and phosphorylation status of downstream signaling molecules in T-ALL cell lines and Ba/F3 clones.

Published
2023

38. Supplementary Figure 1 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 61K, Validation of shRNA constructs.

Published
2023

39. Supplementary Table 1 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 36K, Cell viability profile by RAPID assay.

Published
2023

40. Supplementary Figure 5 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 273K, Confirmation of CD3 expression on OP9 DL1 outgrowth cells.

Published
2023

41. Supplementary Figure 7 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 24K, Effect of JAK kinase inhibitors with varying TYK2-specificity on growth and viability of T-ALL cells.

Published
2023

42. Supplementary Table 6 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

XLSX file - 23K, Clinical, biologic and molecular characteristics of the T-ALL patient samples analyzed. See separate file.

Published
2023

43. Supplementary Figure 8 from TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Author

A. Thomas Look, Brian J. Druker, Louis M. Staudt, Andrew P. Weng, Catriona H.M. Jamieson, Nathanael S. Gray, Mathias Müller, Richard Moriggl, Ross L. Levine, Donna S. Neuberg, Michelle A. Kelliher, Jessica Tatarek, Yebin Ahn, Maria Kleppe, Yandan Yang, Wenjun Zhou, Angela G. Fleischman, Wenxue Ma, Arla Yost, Bill H. Chang, Jason Glover, Vu N. Ngo, Alejandro Gutierrez, Jeffrey W. Tyner, and Takaomi Sanda

Abstract

PDF file - 105K, Signaling and cell cycle distribution after JAK inhibitor I treatment.

Published
2023

44. Data from Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma

Author

Sarah Nikiforow, Jerome Ritz, Glenn Dranoff, Robert Soiffer, Donna S. Neuberg, Richard M. Stone, Nikhil C. Munshi, Kristen Cummings, Heidi DiPietro, Ilene Galinsky, Frédéric F. Lehmann, David E. Gilham, Charles L. Sentman, Jake Reder, Adam Schmucker, Joanina K. Gicobi, Helene Trebeden-Negre, Heather Daley, Lillian Werner, Joana Murad, and Susanne H. Baumeister

Abstract

NKG2D ligands are widely expressed in solid and hematologic malignancies but absent or poorly expressed on healthy tissues. We conducted a phase I dose-escalation study to evaluate the safety and feasibility of a single infusion of NKG2D-chimeric antigen receptor (CAR) T cells, without lymphodepleting conditioning in subjects with acute myeloid leukemia/myelodysplastic syndrome or relapsed/refractory multiple myeloma. Autologous T cells were transfected with a γ-retroviral vector encoding a CAR fusing human NKG2D with the CD3ζ signaling domain. Four dose levels (1 × 106–3 × 107 total viable T cells) were evaluated. Twelve subjects were infused [7 acute myeloid leukemia (AML) and 5 multiple myeloma]. NKG2D-CAR products demonstrated a median 75% vector-driven NKG2D expression on CD3+ T cells. No dose-limiting toxicities, cytokine release syndrome, or CAR T cell–related neurotoxicity was observed. No significant autoimmune reactions were noted, and none of the ≥ grade 3 adverse events were attributable to NKG2D-CAR T cells. At the single injection of low cell doses used in this trial, no objective tumor responses were observed. However, hematologic parameters transiently improved in one subject with AML at the highest dose, and cases of disease stability without further therapy or on subsequent treatments were noted. At 24 hours, the cytokine RANTES increased a median of 1.9-fold among all subjects and 5.8-fold among six AML patients. Consistent with preclinical studies, NKG2D-CAR T cell–expansion and persistence were limited. Manufactured NKG2D-CAR T cells exhibited functional activity against autologous tumor cells in vitro, but modifications to enhance CAR T-cell expansion and target density may be needed to boost clinical activity.

Published
2023

45. Figure S1 from Phase I Trial of Autologous CAR T Cells Targeting NKG2D Ligands in Patients with AML/MDS and Multiple Myeloma

Author

Sarah Nikiforow, Jerome Ritz, Glenn Dranoff, Robert Soiffer, Donna S. Neuberg, Richard M. Stone, Nikhil C. Munshi, Kristen Cummings, Heidi DiPietro, Ilene Galinsky, Frédéric F. Lehmann, David E. Gilham, Charles L. Sentman, Jake Reder, Adam Schmucker, Joanina K. Gicobi, Helene Trebeden-Negre, Heather Daley, Lillian Werner, Joana Murad, and Susanne H. Baumeister

Abstract

NKG2D-CAR T Cell Product Transduction Assessment

Published
2023

46. Supplementary Table 2 from Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status

Author

Scott J. Rodig, Margaret A. Shipp, Donna S. Neuberg, Richard T. Hoppe, Daphne de Jong, Bjoern Chapuy, Sarah E. Daadi, Christopher D. Carey, Christine J. Pak, Courtney F. Connelly, Azra H. Ligon, Yasodha Natkunam, Geraldine S. Pinkus, Robert A. Redd, Ranjana H. Advani, and Margaretha G.M. Roemer

Abstract

Outcome (progression-free survival) - Cox multivariable models for beta2M

Published
2023

47. Supplementary Figure 1.Optimization IHC on pilot series of cHL cases. from Classical Hodgkin Lymphoma with Reduced β2M/MHC Class I Expression Is Associated with Inferior Outcome Independent of 9p24.1 Status

Author

Scott J. Rodig, Margaret A. Shipp, Donna S. Neuberg, Richard T. Hoppe, Daphne de Jong, Bjoern Chapuy, Sarah E. Daadi, Christopher D. Carey, Christine J. Pak, Courtney F. Connelly, Azra H. Ligon, Yasodha Natkunam, Geraldine S. Pinkus, Robert A. Redd, Ranjana H. Advani, and Margaretha G.M. Roemer

Abstract

Three distinct patterns of staining of HRS cell membranes were observed relative to the staining of reactive inflammatory cells: "positive" (Pos), "decreased" (Dec) and "negative" (Neg) for β2M, MHC class I and MHC class II. CHL #1: β2M and MHC class I positive, MHC class II negative; cHL #2: beta2M and MHC class I decreased, MHC class II positive; cHL #3: beta2M and MHC class I negative, MHC class II decreased. Black arrows highlight individual HRS cells or two adjacent HRS cells with distinct patterns of membrane staining, as indicated.

Published
2023

48. Supplementary Figure 5 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Author

Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons

Abstract

Verification of detection power calculation. Comparison between the predicted detection power of 18 replicates and the actual fraction of those replicates that were called MRD+. 18 independent samples from a 1:100k dilution were probed with a 488 SNV panel (see methods). Replicates had their duplex consensus reads downsampled in increments of 10% and detection power was recalculated. Reported are the median and range of predicted detection powers for all replicates at each downsampling.

Published
2023

50. Supplementary Figure 2 from Sensitive Detection of Minimal Residual Disease in Patients Treated for Early-Stage Breast Cancer

Author

Viktor A. Adalsteinsson, Todd R. Golub, Erica L. Mayer, Ann H. Partridge, G. Mike Makrigiorgos, J. Christopher Love, Ian Krop, Nancy U. Lin, Matthew Meyerson, Eric P. Winer, Gad Getz, Atish D. Choudhury, Daniel G. Stover, Gavin Ha, Nikhil Wagle, Niall J. Lennon, Samuel S. Freeman, Matthew DeFelice, Donna S. Neuberg, Carrie Cibulskis, Lorenzo Trippa, Brendan Blumenstiel, Kathy D. Miller, Laura C. Collins, Shoshana M. Rosenberg, Melissa E. Hughes, Ka Wai Leong, Mariana Fitarelli-Kiehl, Fangyan Yu, Ofir Cohen, Denisse Rotem, Gregory J. Kirkner, Mark Fleharty, Tianyu Li, Christopher C. Lo, Kan Xiong, Pedro Exman, Priyanka Ram, Gregory Gydush, Sarah C. Reed, Justin Rhoades, and Heather A. Parsons

Abstract

Early stage breast cancer cohort. (A) Overview of subtype distribution of cohort as well as the timing of blood draws relative to surgery and treatment. (B) REMARK diagram of the early stage breast cancer cohort. (C) Distribution of the number of mutations tracked for each patient.

Published
2023

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