CV

Publications

• Preprint: Pentose Phosphate Pathway Inhibition activates Macrophages towards phagocytic Lymphoma Cell Clearance

  Macrophages in the B-cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition by specific compounds and…

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• Tislelizumab plus zanubrutinib for Richter transformation: the phase 2 RT1 trial

  In patients with chronic lymphocytic leukemia, Richter transformation (RT) reflects the development of an aggressive lymphoma that is associated with poor response to chemotherapy and short survival. We initiated an international, investigator-initiated, prospective, open-label phase 2 study in…

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• Role of the tumor microenvironment in CLL pathogenesis

  Chronic lymphocytic leukemia (CLL) cells extensively interact with and depend on their surrounding tumor microenvironment (TME). The TME encompasses a heterogeneous array of cell types, soluble signals, and extracellular vesicles, which contribute significantly to CLL pathogenesis. CLL cells and the…

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• An anti-CD19/CTLA-4 switch improves efficacy and selectivity of CAR T cells targeting CD80/86-upregulated DLBCL

  himeric antigen receptor T cell (CAR T) therapy is a potent treatment for relapsed/refractory (r/r) B cell lymphomas but provides lasting remissions in only ∼40% of patients and is associated with serious adverse events. We identify an upregulation of CD80 and/or CD86 in tumor tissue of (r/r)…

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• Entirely noninvasive outcome prediction in central nervous system lymphomas using circulating tumor DNA

  State-of-the-art response assessment of central nervous system lymphoma (CNSL) by magnetic resonance imaging is challenging and an insufficient predictor of treatment outcomes. Accordingly, the development of novel risk stratification strategies in CNSL is a high unmet medical need. We applied…

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• Targeting the tumor microenvironment for treating double refractory chronic lymphocytic leukemia

  The introduction of BTK inhibitors and BCL2 antagonists to the treatment of chronic lymphocytic leukemia has revolutionized therapy and improved patient outcomes. These agents have replaced chemoimmunotherapy as standard of care. Despite this progress, a new group of patients is currently emerging,…

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• Impact of leukemia-associated macrophages on the progression and therapy response of chronic lymphocytic leukemia

  The treatment landscape of chronic lymphocytic leukemia (CLL) has advanced remarkably over the past decade. The advent and approval of the BTK inhibitor ibrutinib and BCL-2 inhibitor venetoclax, as well as monoclonal anti-CD20 antibodies rituximab and obinutuzumab, have resulted in deep remissions…

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• First-Line Venetoclax Combinations in Chronic Lymphocytic Leukemia

  BACKGROUND Randomized trials of venetoclax plus anti-CD20 antibodies as first-line treatment in fit patients (i.e., those with a low burden of coexisting conditions) with advanced chronic lymphocytic leukemia (CLL) have been lacking. METHODS In a phase 3, open-label trial, we randomly assigned,…

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• LYN kinase programs stromal fibroblasts to facilitate leukemic survival via regulation of c-JUN and THBS1

  Microenvironmental bystander cells are essential for the progression of chronic lymphocytic leukemia (CLL). We have discovered previously that LYN kinase promotes the formation of a microenvironmental niche for CLL. Here we provide mechanistic evidence that LYN regulates the polarization of stromal…

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• Efficacy and Safety of the Combination of Tirabrutinib and Entospletinib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia

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• Transcriptomic profiles and 5-year results from the randomized CLL14 study of venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab in chronic lymphocytic leukemia

  Data on long-term outcomes and biological drivers associated with depth of remission after BCL2 inhibition by venetoclax in the treatment of chronic lymphocytic leukemia (CLL) are limited. In this open-label parallel-group phase-3 study, 432 patients with previously untreated CLL were randomized…

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• The scaffold protein NEDD9 is necessary for leukemia-cell migration and disease progression in a mouse model of chronic lymphocytic leukemia

  The scaffold protein NEDD9 is frequently upregulated and hyperphosphorylated in cancers, and is associated with poor clinical outcome. NEDD9 promotes B-cell adhesion, migration and chemotaxis, pivotal processes for malignant development. We show that global or B-cell-specific deletion of Nedd9 in…

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• Constitutive activation of Lyn kinase enhances BCR responsiveness, but not the development of CLL in Eµ-TCL1 mice

  The treatment of chronic lymphocytic leukemia (CLL) has been improved dramatically by inhibitors targeting B-cell receptor (BCR)-associated kinases. The tyrosine kinase Lyn is a key modulator of BCR signaling and shows increased expression and activity in CLL. To evaluate the functional relevance of…

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• Meta-Analysis Reveals Significant Sex Differences in Chronic Lymphocytic Leukemia Progression in the Eµ-TCL1 Transgenic Mouse Model

  The Eµ-TCL1 transgenic mouse model represents the most widely and extensively used animal model for chronic lymphocytic leukemia (CLL). In this report, we performed a meta-analysis of leukemia progression in over 300 individual Eµ-TCL1 transgenic mice and discovered a significantly accelerated…

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• New roles for B cell receptor associated kinases: when the B cell is not the target

  Targeting of B cell receptor associated kinases (BAKs), such as Bruton’s tyrosine kinase (BTK) or phosphoinositol-3-kinase (PI3K) delta, by specific inhibitors has revolutionized the therapy of B lymphoid malignancies. BAKs are critical signaling transducers of BCR signaling and seem relevant in B…

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• Extracellular vesicle measurements with nanoparticle tracking analysis - An accuracy and repeatability comparison between NanoSight NS300 and ZetaView

  The expanding field of extracellular vesicle (EV) research needs reproducible and accurate methods to characterize single EVs. Nanoparticle Tracking Analysis (NTA) is commonly used to determine EV concentration and diameter. As the EV field is lacking methods to easily confirm and validate NTA data,…

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• Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors

  Single-agent immunotherapy has shown remarkable efficacy in selected cancer entities and individual patients. However, most patients fail to respond. This is likely due to diverse immunosuppressive mechanisms acting in a concerted way to suppress the host anti-tumor immune response. Combination…

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• Evaluation of a Prognostic Epigenetic Classification System in Chronic Lymphocytic Leukemia Patients

  Methylation at 5 CpG sites was previously shown to classify chronic lymphocytic leukemia (CLL) into 3 prognostic subgroups. Here, we aimed to validate the marker set in an additional cohort and to evaluate its clinical utility for CLL patient stratification. We evaluated this epigenetic marker set…

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• Altered DNA Methylation Profiles in SF3B1 Mutated CLL Patients

  Mutations in splicing factor genes have a severe impact on the survival of cancer patients. Splicing factor 3b subunit 1 (SF3B1) is one of the most frequently mutated genes in chronic lymphocytic leukemia (CLL); patients carrying these mutations have a poor prognosis. Since the splicing machinery…

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• Inhibition of Tumor VEGFR2 Induces Serine 897 EphA2-Dependent Tumor Cell Invasion and Metastasis in NSCLC

  Anti-angiogenic treatment targeting vascular endothelial growth factor (VEGF)-VEGFR2 signaling has shown limited efficacy in lung cancer patients. Here, we demonstrate that inhibition of VEGFR2 in tumor cells, expressed in ∼20% of non-squamous non-small cell lung cancer (NSCLC) patients, leads to a…

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• Efficacy and Safety of Tirabrutinib and Idelalisib With or Without Obinutuzumab in Relapsed Chronic Lymphocytic Leukemia

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• Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials

  Richter transformation (RT) is defined as development of aggressive lymphoma in patients (pts) with CLL. The incidence rates of RT among pts with CLL range from 2 to 10%. The aim of this analysis is to report the frequency, characteristics and outcomes of pts with RT enrolled in trials of the…

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• Residual abdominal lymphadenopathy after intensive frontline chemoimmunotherapy is associated with inferior outcome independently of minimal residual disease status in chronic lymphocytic leukemia

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• Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG)

  Fludarabine, cyclophosphamide and rituximab (FCR) was compared to bendamustine and rituximab (BR) in an international, randomized, open label, phase 3 trial in 561 previously untreated, fit patients with chronic lymphocytic leukemia (CLL) without del (17p). Primary endpoint was progression free…

• Extracellular vesicles and PD-L1 suppress macrophages, inducing therapy resistance in TP53-deficient B-cell malignancies

  Genetic alterations in the DNA damage response (DDR) pathway are a frequent mechanism of resistance to chemoimmunotherapy (CIT) in B-cell malignancies. We have previously shown that the synergy of CIT relies on secretory crosstalk elicited by chemotherapy between the tumor cells and macrophages.…

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• Venetoclax plus rituximab or obinutuzumab after allogeneic hematopoietic stem cell transplantation in chronic lymphocytic leukemia

  For several decades, allogeneic hematopoietic stem cell transplantation (alloHCT) has been a therapeutic option in patients with chronic lymphocytic leukemia (CLL) with high-risk features such as del(17p) and/or TP53 mutations, complex aberrant karyotype, or chemotherapy-resistant disease. With the…

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• Active Akt signaling triggers CLL toward Richter transformation via overactivation of Notch1

  Richter's transformation (RT) is an aggressive lymphoma that occurs upon progression from chronic lymphocytic leukemia (CLL). Transformation has been associated with genetic aberrations in the CLL phase involving TP53, CDKN2A, MYC, and NOTCH1; however, a significant proportion of RT cases lack CLL…

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• Distinct Genetically Determined Origins of Myd88/BCL2-Driven Aggressive Lymphoma Rationalize Targeted Therapeutic Intervention Strategies

  Genomic profiling revealed the identity of at least 5 subtypes of diffuse large B-cell lymphoma (DLBCL), including the MCD/C5 cluster characterized by aberrations in MYD88, BCL2, PRDM1, and/or SPIB. We generated mouse models harboring B cell–specific Prdm1 or Spib aberrations on the background of…

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• High efficacy of venetoclax plus obinutuzumab in patients with complex karyotype and chronic lymphocytic leukemia

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• Deregulation and epigenetic modification of BCL2-family genes cause resistance to venetoclax in hematologic malignancies

  The BCL2 inhibitor venetoclax has been approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax…

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