11 results on '"Magdalena Hinterbrandner"'
Search Results
2. Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells
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Magdalena Hinterbrandner, Viviana Rubino, Carina Stoll, Stefan Forster, Noah Schnüriger, Ramin Radpour, Gabriela M. Baerlocher, Adrian F. Ochsenbein, and Carsten Riether
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Hematology ,Stem cells ,Medicine - Abstract
Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by CD8+ cytotoxic T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML BM, protected LSCs from MHC class I–dependent CD8+ CTL–mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4 signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL–mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulators of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost antileukemic immunity in CML.
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- 2021
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3. Tnfrsf4-expressing regulatory T cells promote immune escape of chronic myeloid leukemia stem cells
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Carina Stoll, Stefan Forster, Adrian F. Ochsenbein, Magdalena Hinterbrandner, Noah Schnüriger, Carsten Riether, Viviana Rubino, Gabriela M. Baerlocher, and Ramin Radpour
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Male ,medicine.medical_treatment ,610 Medicine & health ,chemical and pharmacologic phenomena ,Cancer immunotherapy ,Stem cells ,Biology ,T-Lymphocytes, Regulatory ,03 medical and health sciences ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Leukemias ,medicine ,Cytotoxic T cell ,Animals ,Humans ,030304 developmental biology ,0303 health sciences ,Myeloid leukemia ,FOXP3 ,hemic and immune systems ,General Medicine ,Hematology ,Receptors, OX40 ,medicine.disease ,3. Good health ,Leukemia ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Chronic Disease ,Cancer research ,Female ,Tumor Escape ,Bone marrow ,Immunotherapy ,Stem cell ,CD8 ,Research Article - Abstract
Leukemia stem cells (LSCs) promote the disease and seem resistant to therapy and immune control. Why LSCs are selectively resistant against elimination by cytotoxic CD8+ T cells (CTLs) is still unknown. In this study, we demonstrate that LSCs in chronic myeloid leukemia (CML) can be recognized and killed by CD8+ CTLs in vitro. However, Tregs, which preferentially localized close to CD8+ CTLs in CML bone marrow (BM), protected LSCs from MHC-class I dependent CD8+ CTL-mediated elimination in vivo. BM Tregs in CML were characterized by the selective expression of tumor necrosis factor receptor 4 (Tnfrsf4). Stimulation of Tnfrsf4-signaling did not deplete Tregs but reduced the capacity of Tregs to protect LSCs from CD8+ CTL-mediated killing. In the BM of newly diagnosed CML patients, TNFRSF4 mRNA levels were significantly increased and correlated with the expression of the Treg-restricted transcription factor FOXP3. Overall, these results identify Tregs as key regulator of immune escape of LSCs and TNFRSF4 as a potential target to reduce the function of Tregs and boost anti-leukemic immunity in CML.
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- 2021
4. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents
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Adrian F. Ochsenbein, Ulrike Bacher, Hans de Haard, Ellen Erzeel, David Francisco, Anna Hultberg, Samson Fung, Magdalena Hinterbrandner, Markus G. Manz, Yara Banz, Mahan Moshir, Thomas Pabst, Tim Delahaye, Luc Van Rompaey, Sabine Höpner, Rouven Müller, Carsten Riether, Domenica Gandini, Walid H. Gharib, Rémy Bruggmann, Nicolas Leupin, University of Zurich, Riether, Carsten, and Ochsenbein, Adrian F
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid ,Combination therapy ,Azacitidine ,Antineoplastic Agents ,Apoptosis ,610 Medicine & health ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,1300 General Biochemistry, Genetics and Molecular Biology ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Humans ,Medicine ,CD70 ,business.industry ,Antibodies, Monoclonal ,Myeloid leukemia ,General Medicine ,DNA Methylation ,medicine.disease ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,Clinical trial ,Leukemia, Myeloid, Acute ,Leukemia ,Treatment Outcome ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,10032 Clinic for Oncology and Hematology ,Neoplastic Stem Cells ,570 Life sciences ,biology ,Stem cell ,business ,CD27 Ligand ,medicine.drug - Abstract
Acute myeloid leukemia (AML) is driven by leukemia stem cells (LSCs) that resist conventional chemotherapy and are the major cause of relapse1,2. Hypomethylating agents (HMAs) are the standard of care in the treatment of older or unfit patients with AML, but responses are modest and not durable3-5. Here we demonstrate that LSCs upregulate the tumor necrosis factor family ligand CD70 in response to HMA treatment resulting in increased CD70/CD27 signaling. Blocking CD70/CD27 signaling and targeting CD70-expressing LSCs with cusatuzumab, a human αCD70 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity activity, eliminated LSCs in vitro and in xenotransplantation experiments. Based on these preclinical results, we performed a phase 1/2 trial in previously untreated older patients with AML with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine (NCT03030612). We report results from the phase 1 dose escalation part of the clinical trial. Hematological responses in the 12 patients enrolled included 8 complete remission, 2 complete remission with incomplete blood count recovery and 2 partial remission with 4 patients achieving minimal residual disease negativity by flow cytometry at
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- 2020
5. Eosinophils regulate adipose tissue inflammation and sustain physical and immunological fitness in old age
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Noemi Zbären, Neill R. Graff-Radford, Peter M. Villiger, Alicia Shiu, Mario Noti, Johan Auwerx, Pascal Guntern, Zhaoqing Ding, Norman Moullan, Federico Storni, Hanadie Yousef, Joseph M. Castellano, Alexander Eggel, Denis Grandgirard, Markus Britschgi, Wilhelm Hofstetter, Magdalena Hinterbrandner, Robin van Brummelen, Mark Siegrist, Stephen L. Leib, Pascal Gasser, Daniel Brigger, Saul A. Villeda, Kira I. Mosher, Tony Wyss-Coray, and Carsten Riether
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Adoptive cell transfer ,Aging ,Endocrinology, Diabetes and Metabolism ,rejuvenation ,Adipose tissue ,White ,Inbred C57BL ,stem-cells ,Mice ,perspectives ,Medicine ,Homeostasis ,610 Medicine & health ,t-cells ,Middle Aged ,macrophages ,Satellite Cells ,medicine.anatomical_structure ,Adipose Tissue ,caloric restriction ,medicine.symptom ,Adult ,Satellite Cells, Skeletal Muscle ,Skeletal Muscle ,Adipose Tissue, White ,Inflammation ,Article ,insulin-resistance ,Young Adult ,Immune system ,Immunity ,increase ,Physiology (medical) ,expression ,Internal Medicine ,Animals ,Humans ,Muscle Strength ,Obesity ,Aged ,Nutrition ,life-span ,business.industry ,Cell Biology ,Eosinophil ,Glucose Tolerance Test ,Mice, Inbred C57BL ,Eosinophils ,Gene Expression Regulation ,Ageing ,Physical Fitness ,Immunology ,570 Life sciences ,biology ,Interleukin-4 ,business - Abstract
Adipose tissue eosinophils (ATEs) are important in the control of obesity-associated inflammation and metabolic disease. However, the way in which ageing impacts the regulatory role of ATEs remains unknown. Here, we show that ATEs undergo major age-related changes in distribution and function associated with impaired adipose tissue homeostasis and systemic low-grade inflammation in both humans and mice. We find that exposure to a young systemic environment partially restores ATE distribution in aged parabionts and reduces adipose tissue inflammation. Approaches to restore ATE distribution using adoptive transfer of eosinophils from young mice into aged recipients proved sufficient to dampen age-related local and systemic low-grade inflammation. Importantly, restoration of a youthful systemic milieu by means of eosinophil transfers resulted in systemic rejuvenation of the aged host, manifesting in improved physical and immune fitness that was partially mediated by eosinophil-derived IL-4. Together, these findings support a critical function of adipose tissue as a source of pro-ageing factors and uncover a new role of eosinophils in promoting healthy ageing by sustaining adipose tissue homeostasis.
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- 2020
6. CD70/CD27 signaling promotes blast stemness and is a viable therapeutic target in acute myeloid leukemia
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Anne Laure Huguenin, Sabine Hoepner, Magdalena Hinterbrandner, Elias D. Bührer, Thomas Pabst, Christian M. Schürch, Ramin Radpour, Adrian F. Ochsenbein, Carsten Riether, and Inti Zlobec
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0301 basic medicine ,Myeloid ,Immunology ,610 Medicine & health ,chemical and pharmacologic phenomena ,Protein Serine-Threonine Kinases ,Biology ,Article ,Germinal Center Kinases ,Mice ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Precursor cell ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,Immunology and Allergy ,Progenitor cell ,Wnt Signaling Pathway ,neoplasms ,Research Articles ,Aged ,Wnt signaling pathway ,Antibodies, Monoclonal ,Myeloid leukemia ,hemic and immune systems ,Middle Aged ,TNF Receptor-Associated Factor 2 ,medicine.disease ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,3. Good health ,Leukemia, Myeloid, Acute ,Haematopoiesis ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,570 Life sciences ,biology ,Stem cell ,Blast Crisis ,CD27 Ligand ,Signal Transduction - Abstract
Riether et al. show that CD70/CD27 signaling activates stem cell gene expression programs in acute myeloid leukemia (AML). Blocking the CD70/CD27 interaction inhibits self-renewal and induces differentiation of AML blasts and stem/progenitor cells., Aberrant proliferation, symmetric self-renewal, increased survival, and defective differentiation of malignant blasts are key oncogenic drivers in acute myeloid leukemia (AML). Stem cell gene signatures predict poor prognosis in AML patients; however, with few exceptions, these deregulated molecular pathways cannot be targeted therapeutically. In this study, we demonstrate that the TNF superfamily ligand–receptor pair CD70/CD27 is expressed on AML blasts and AML stem/progenitor cells. CD70/CD27 signaling in AML cells activates stem cell gene expression programs, including the Wnt pathway, and promotes symmetric cell divisions and proliferation. Soluble CD27, reflecting the extent of CD70/CD27 interactions in vivo, was significantly elevated in the sera of newly diagnosed AML patients and is a strong independent negative prognostic biomarker for overall survival. Blocking the CD70/CD27 interaction by mAb induced asymmetric cell divisions and differentiation in AML blasts and AML stem/progenitor cells, inhibited cell growth and colony formation, and significantly prolonged survival in murine AML xenografts. Importantly, hematopoietic stem/progenitor cells from healthy BM donors express neither CD70 nor CD27 and were unaffected by blocking mAb treatment. Therefore, targeting CD70/CD27 signaling represents a promising therapeutic strategy for AML.
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- 2016
7. TNIK signaling imprints CD8
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Carla A, Jaeger-Ruckstuhl, Magdalena, Hinterbrandner, Sabine, Höpner, Colin E, Correnti, Ursina, Lüthi, Olivier, Friedli, Stefan, Freigang, Mohamad F, Al Sayed, Elias D, Bührer, Michael A, Amrein, Christian M, Schürch, Ramin, Radpour, Carsten, Riether, and Adrian F, Ochsenbein
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Mice, Knockout ,Apoptosis ,Cell Differentiation ,CD8-Positive T-Lymphocytes ,Lymphocytic Choriomeningitis ,Protein Serine-Threonine Kinases ,Signal transduction ,Lymphocyte Activation ,Immunological memory ,Article ,Mice ,Viral infection ,Animals ,Humans ,Lymphocytic choriomeningitis virus ,CD8-positive T cells ,Immunologic Memory ,Wnt Signaling Pathway - Abstract
Co-stimulatory signals, cytokines and transcription factors regulate the balance between effector and memory cell differentiation during T cell activation. Here, we analyse the role of the TRAF2-/NCK-interacting kinase (TNIK), a signaling molecule downstream of the tumor necrosis factor superfamily receptors such as CD27, in the regulation of CD8+ T cell fate during acute infection with lymphocytic choriomeningitis virus. Priming of CD8+ T cells induces a TNIK-dependent nuclear translocation of β-catenin with consecutive Wnt pathway activation. TNIK-deficiency during T cell activation results in enhanced differentiation towards effector cells, glycolysis and apoptosis. TNIK signaling enriches for memory precursors by favouring symmetric over asymmetric cell division. This enlarges the pool of memory CD8+ T cells and increases their capacity to expand after re-infection in serial re-transplantation experiments. These findings reveal that TNIK is an important regulator of effector and memory T cell differentiation and induces a population of stem cell-like memory T cells., Coordinate expression of multiple factors play critical roles in the regulation between effector and memory CD8+ T cell differentiation. Here the authors show upon acute viral infection TNIK is critically required as a regulator of effector and memory T cell differentiation.
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- 2019
8. Targeting CD70 with Cusatuzumab Eliminates Acute Myeloid Leukemia Stem Cells in Humans
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Walid H. Gharib, Rouven Müller, Samson Fung, Mahan Moshir, Tim Delahaye, Yara Banz, Hans de Haard, Thomas Pabst, Rémy Bruggmann, Adrian F. Ochsenbein, Ellen Erzeel, Luc Van Rompaey, Sabine Höpner, Markus G. Manz, Carsten Riether, David Francisco, Nicolas Leupin, Domenica Gandini, Vera Ulrike Bacher, Magdalena Hinterbrandner, and Anna Hultberg
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Palliative care ,business.industry ,Immunology ,Azacitidine ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Leukemia ,medicine.anatomical_structure ,Precursor cell ,medicine ,Cytarabine ,Cancer research ,Bone marrow ,Stem cell ,business ,medicine.drug - Abstract
Introduction Acute myeloid leukemia (AML) is a heterogenous hematological malignancy driven by leukemia stem cells (LSCs) (Lapidot et al, 1994). LSCs resistant against conventional chemotherapy represent the major cause of relapse. Elderly or unfit AML patients not eligible for intensive chemotherapy are treated in a palliative setting with hypomethylating agents (HMA) or low dose Ara-C, but responses are modest and not durable. The reason for the low efficacy of HMA treatment is their insufficient action on the disease initiating- and -maintaining LSC population (Craddock et al, 2013). We recently demonstrated that CD34+ AML cells (progenitors and LSC) consistently express the tumor necrosis factor family ligand CD70 as well as its receptor CD27 and that cell-autonomous CD70/CD27-signaling propagates the disease (Riether et al. 2017). The aim of the current study was to evaluate whether resistance to HMA treatment can be overcome by combining HMA with an anti-CD70 monoclonal antibody treatment. Experimental design The effect of HMA treatment on the expression of CD70 on primary human CD34+CD38- AML LSCs was determined in vitro cultures and in patients treated with HMA in vivo. The therapeutic potential of targeting CD70-expressing LSCs in presence and absence of HMA was assessed using the anti-CD70 ADCC-optimized monoclonal antibody (mAb), cusatuzumab, and an effector-dead anti-CD70 mAb in colony formation and re-plating assays as well as patient-derived xenograft models (Silence et al, 2014). The clinical relevance of the findings was determined in a clinical phase 1 trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with the HMA azacitidine (AZA, NCT03030612). Four different dose levels of cusatuzumab (1, 3, 10 and 20 mg/kg Q2W) were studied; AZA was administered at 75 mg/m² for 7 days every 28 days. Results We found that resistance of AML LSCs to HMA treatment is mediated by the up-regulation of the CD70. The up-regulation of CD70 triggered cell-autonomous CD70/CD27 signaling on AML LSCs. Based on these findings we hypothesized that the upregulation of CD70 by HMA may render LSCs more susceptible to CD70-targeting interventions. Targeting CD70-expressing LSCs by a blocking anti-CD70 mAb and the anti-CD70 mAb cusatuzumab, which blocks CD70/CD27-signaling and additionally mediates ADCC and CDC, eradicated LSCs in colony and re-plating assays in vitro and in xenotransplantation experiments in vivo. HMA in combination with blocking αCD70 mAb synergistically reduced LSC numbers in vivo and this was even more efficient when ADCC-enhanced αCD70 mAb cusatuzumab was added in the presence of NK cells. In order to test the hypothesis that targeting CD70 in combination with HMA eliminates LSCs in AML patients, we initiated a phase 1 dose-escalation trial in previously untreated elderly AML patients with a single dose of cusatuzumab monotherapy followed by a combination therapy with azacitidine. No dose-limiting toxicities (DLT) were observed in the dose-escalation phase 1 trial and responses were observed across the dose levels (1-20 mg/kg). A single dose of cusatuzumab reduced bone marrow blasts in just two weeks in all patients on average by 32%. Cusatuzumab monotherapy significantly reduced LSC numbers and frequencies in all patients analyzed in the bone marrow as assessed in limiting dilution colony assays. Single cell sequencing analysis revealed that cusatuzumab induced gene signatures related to myeloid differentiation and apoptosis in LSCs. In combination with azacitidine, cusatuzumab induced CR/CRi in 10 out of 12 patients. Responses were observed at all dose levels of cusatuzumab and median time to response was 3.3 months. Conclusions Blocking CD70/CD27-signaling and targeting CD70-expressing LSCs by the ADCC-optimized mAb, cusatuzumab, eliminated LSCs in vitro and in xenotransplantation experiments. In a phase 1 study promising activity of cusatuzumab in combination with HMA was observed in AML patients, in which translational data indicate that cusatuzumab selectively eliminates CD70-expressing LSCs. Disclosures Van Rompaey: argenx: Employment, Equity Ownership, Patents & Royalties. Moshir:Argenx: Employment, Equity Ownership. Delahaye:argenx: Employment, Equity Ownership. Gandini:Argenx: Employment, Equity Ownership. Erzeel:argenx: Employment, Equity Ownership. Hultberg:Argenx: Employment. Fung:argenx: Consultancy, Equity Ownership. De Haard:Argenx: Employment, Equity Ownership, Patents & Royalties. Leupin:Argenx: Employment, Equity Ownership, Patents & Royalties.
- Published
- 2019
9. Argx-110 Targeting CD70, in Combination with Azacitidine, Shows Favorable Safety Profile and Promising Anti-Leukemia Activity in Newly Diagnosed AML Patients in an Ongoing Phase 1/2 Clinical Trial
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Yara Banz, Samson Fung, Markus G. Manz, Carsten Riether, Sabine Höpner, Hans de Haard, Tim Delahaye, Anna Hultberg, Thomas Pabst, Adrian F. Ochsenbein, Domenica Gandini, Mahan Moshir, Rouven Müller, Luc Van Rompaey, Ulrike Bacher, Ellen Erzeel, Mario Bargetzi, Magdalena Hinterbrandner, and Nicolas Leupin
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,Myeloid ,medicine.medical_treatment ,Immunology ,Azacitidine ,Hematopoietic stem cell transplantation ,Biochemistry ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Medicine ,business.industry ,Myeloid leukemia ,Cell Biology ,Hematology ,medicine.disease ,Chemotherapy regimen ,Clinical trial ,Transplantation ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,business ,medicine.drug - Abstract
Outcomes in elderly patients with acute myeloid leukemia (AML) are still adverse, as the majority does not qualify for intensive therapy or allogenic stem cell transplantation (ASCT). DNA hypomethylating agents (HMAs) induce remissions and prolong survival in a fraction of these patients. However, overall prognosis remains dismal and all patients progress due to therapy-resistant leukemia stem cells (LSCs). We recently demonstrated that HMAs upregulate the expression of CD70 on primary human AML LSCs, potentially contributing to HMA resistance and that blocking the cell-autonomous CD70/CD27 signaling inhibits proliferation and myeloid differentiation of LSCs and contributes to HMA resistance. Consequently, combining HMA treatment with a blocking αCD70 monoclonal antibody potently reduced colony formation of AML LSCs in vitro and effectively eliminated human AML LCSs in xenograft experiments. Based on these results, we initiated an open-label, non-controlled, non-randomized Phase 1/2 trial combining the HMA azacitidine (AZA) with ARGX-110, a human monoclonal antibody targeting CD70, in newly diagnosed AML patients unfit for intensive chemotherapy (ARGX-110-1601, NCT03030612). Trial design ARGX-110 with optimized antibody-dependent cell-mediated cytotoxicity (ADCC), is administered intravenously at 1, 3, 10 or 20 mg/kg once every two weeks (Q2W), in combination with a standard dose of AZA (75 mg/m² subcutaneously for 7 days every 28 days). A 2-week lead-in of ARGX-110 enables studying the effect of αCD70 antibody monotherapy. Primary objectives in the Phase 1 include determining the maximum tolerated dose of ARGX-110 in combination with AZA and the recommended phase 2 dose (RP2D). Secondary objectives comprise safety, pharmacokinetics and anti-leukemic activity of ARGX-110 alone or in combination with AZA (including overall response rate (ORR), frequencies of LSCs and minimal/measurable residual disease (MRD)). Results The trial is ongoing and as of 16th July 2018, 12 newly diagnosed AML patients were treated in the dose-escalation part of the trial, the results of which will be further updated in December 2018. The median age over the dose cohorts was 75 years (range 64-84) and included intermediate (N=6) and adverse (N=6) ELN risk groups. WHO subtypes were AML with recurrent genetic abnormalities (N=2), MDS-related changes (N=6), AML-NOS (N=3) and therapy-related myeloid neoplasms (N=1). No dose-limiting toxicity was observed and the combination of ARGX-110 with a standard dose of AZA was well tolerated. Hematological toxicities, in line with expected AZA toxicities, were the most frequently reported adverse events (AEs). At the cut-off, the ORR (complete remission [CR] + incomplete recovery [CRi] + partial remission [PR] + morphologic leukemia-free status [MLFS]) was 92% (11/12 patients); among the 11 evaluable subjects, the best response was CR/CRi for 9 patients (82%), 1 patient (9%) reached MLFS, and 1 (9%) PR, with 7 patients still on the trial (median duration on the trial at cut-off was 6.9 months [range: 2-14.4 months]). Significantly, 1 patient reached CR and was discontinued after 5 months to undergo ASCT. Five evaluable patients (45%) achieved MRD negativity by flow cytometry. Molecular MRD negativity was achieved in 3/8 patients with available results, two correlating with flow-MRD negativity. The mean time to response for the first 9 patients was 2.8 months and 3.4 months to reach best response. The 3 patients in the 20 mg/kg cohort did not all reach response at the time of cut-off. Based on pharmacokinetics, safety, and pharmacodynamic data, the RP2D of 10 mg/kg was established. Translational studies assessing LSC frequencies in bone marrow aspirates by limiting dilution colony assays and xenograft experiments revealed that ARGX-110 monotherapy and in combination with AZA significantly reduced LSC frequencies in AML patients. Conclusions ARGX-110 in combination with AZA is well tolerated and leads to a higher ORR compared to historical data for AZA alone. Clinical activity of the combination is observed in different AML subtypes and risk categories. Preliminary data indicate that ARGX-110 alone, and in combination with AZA, efficiently eliminates LSCs. These observations warrant further accelerated investigation of ARGX-110 in combination with AZA in AML patients unfit for intensive therapy. Disclosures Ochsenbein: argenx: Research Funding. Riether:argenx: Research Funding. Bacher:argenx: Research Funding. Höpner:argenx: Research Funding. Hinterbrandner:argenx: Research Funding. Van Rompaey:argenx: Employment. Moshir:argenx: Employment. Delahaye:argenx: Employment. Gandini:argenx: Employment. Erzeel:argenx: Employment. Hultberg:argenx: Employment. Fung:argenx: Consultancy. De Haard:argenx: Employment. Leupin:argenx: Employment.
- Published
- 2018
10. Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling
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Ramin Radpour, Adrian F. Ochsenbein, Christoph Flury, Christian M. Schürch, Gabriela M. Baerlocher, Carsten Riether, Linda Drück, Magdalena Hinterbrandner, and Anne-Laure Huguenin
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medicine.drug_class ,Pharmacology ,Tyrosine-kinase inhibitor ,03 medical and health sciences ,Mice ,0302 clinical medicine ,hemic and lymphatic diseases ,Cell Line, Tumor ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,medicine ,Animals ,Humans ,Progenitor cell ,Transcription factor ,Protein Kinase Inhibitors ,Wnt Signaling Pathway ,030304 developmental biology ,0303 health sciences ,business.industry ,Wnt signaling pathway ,General Medicine ,Protein-Tyrosine Kinases ,medicine.disease ,3. Good health ,Tumor Necrosis Factor Receptor Superfamily, Member 7 ,Leukemia ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Neoplastic Stem Cells ,Tumor necrosis factor alpha ,Stem cell ,business ,Neoplasm Transplantation ,Chronic myelogenous leukemia ,CD27 Ligand - Abstract
In chronic myelogenous leukemia (CML), oncogenic BCR-ABL1 activates the Wnt pathway, which is fundamental for leukemia stem cell (LSC) maintenance. Tyrosine kinase inhibitor (TKI) treatment reduces Wnt signaling in LSCs and often results in molecular remission of CML; however, LSCs persist long term despite BCR-ABL1 inhibition, ultimately causing disease relapse. We demonstrate that TKIs induce the expression of the tumor necrosis factor (TNF) family ligand CD70 in LSCs by down-regulating microRNA-29, resulting in reduced CD70 promoter DNA methylation and up-regulation of the transcription factor specificity protein 1. The resulting increase in CD70 triggered CD27 signaling and compensatory Wnt pathway activation. Combining TKIs with CD70 blockade effectively eliminated human CD34(+) CML stem/progenitor cells in xenografts and LSCs in a murine CML model. Therefore, targeting TKI-induced expression of CD70 and compensatory Wnt signaling resulting from the CD70/CD27 interaction is a promising approach to overcoming treatment resistance in CML LSCs.
- Published
- 2015
11. CD70/CD27 Signaling Mediates Resistance of Chronic Myeloid Leukemia Stem Cells to Tyrosine Kinase Inhibitors By Compensatory Activation of the Wnt Pathway
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Christian M. Schürch, Magdalena Hinterbrandner, Ramin Radpour, Adrian F. Ochsenbein, Carsten Riether, and Anne-Laure Huguenin
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ABL ,Immunology ,Wnt signaling pathway ,breakpoint cluster region ,Myeloid leukemia ,Cell Biology ,Hematology ,Biology ,medicine.disease ,Biochemistry ,Leukemia ,hemic and lymphatic diseases ,medicine ,Cancer research ,Stem cell ,Tyrosine kinase ,Chronic myelogenous leukemia - Abstract
The introduction of BCR/ABL-specific tyrosine kinase inhibitors (TKIs) a decade ago revolutionized chronic myelogenous leukemia (CML) therapy. However, disease-initiating leukemia stem cells (LSCs) in CML are resistant to TKIs despite BCR/ABL inhibition. Therefore, CML will ultimately relapse upon drug discontinuation. We have previously shown that blocking CD70/CD27 signaling targets LSCs by inhibiting the activation of the Wnt pathway. Here, we investigated a combination therapy of TKIs and CD70/CD27 blocking monoclonal antibodies in human and murine CML. We demonstrate that TKI-mediated BCR/ABL inhibition down-regulates miR-29, leading to increased expression of specificity protein 1 (SP1), a transcription factor with binding site in the CD70 promoter. In addition, TKI treatment reduced the expression of DNA methyltransferases resulting in de-methylation of the CD70 promoter. These combined effects resulted in CD70 up-regulation on LSCs, enhanced CD70/CD27 signaling and compensatory Wnt pathway activation. Combined BCR/ABL and CD70/CD27 inhibition synergistically reduced Wnt signaling and eradicated leukemia cells in vitro. More importantly, combination therapy effectively eliminated CD34+ CML stem/progenitor cells in murine xenografts and LSCs in a murine CML model. Therefore, TKI-induced CD70 up-regulation triggers CD70/CD27 signaling leading to compensatory Wnt activation. These findings identify an important targetable TKI resistance mechanism of CML LSCs and may lead to new therapeutic strategies to directly target LSCs to overcome treatment resistance. Disclosures No relevant conflicts of interest to declare.
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