245 results on '"Manz MG"'
Search Results
2. Dendritic cell homeostasis is maintained by nonhematopoietic and T-cell-produced Flt3-ligand in steady state and during immune responses
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Saito Y, Boddupalli CS, Borsotti C, and Manz Mg
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CD4-Positive T-Lymphocytes ,Mice, Knockout ,Immunity, Cellular ,Lymphoid Tissue ,Membrane Proteins ,Cell Differentiation ,Mice, Transgenic ,Dendritic Cells ,CD8-Positive T-Lymphocytes ,Hematopoietic Stem Cells ,Mice ,Animals ,Homeostasis ,Cells, Cultured - Abstract
Lymphoid-tissue dendritic cells (DCs) are short-lived and need to be continuously replenished from bone marrow-derived DC progenitor cells. Fms-related tyrosine kinase 3 is expressed during cellular development from hematopoietic progenitors to lymphoid-tissue DCs. Fms-related tyrosine kinase 3 ligand (Flt3L) is an essential, nonredundant cytokine for DC progenitor to lymphoid tissue DC differentiation and maintenance. However, which cells contribute to Flt3L production and how Flt3L cytokine levels are regulated in steady state and during immune reactions remains to be determined. Here we demonstrate that besides nonhematopoietic cells, WT T cells produce Flt3L and contribute to the generation of both classical DCs (cDCs) and plasmacytoid DCs in Flt3L(-/-) mice. Upon stimulation in vitro, CD4(+) T cells produce more Flt3L than CD8(+) T cells. Moreover, in vivo stimulation of naïve OT-II CD4(+) T cells with OVA leads to increase of pre-cDCs and cDCs in draining lymph nodes of Flt3L(-/-) mice in a partially Flt3L-dependent manner. Thus, Flt3L-mediated lymphoid tissue DC homeostasis is regulated by steady-state T cells as well as by proliferative T cells, fostering local development of lymphoid organ resident DCs.
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- 2013
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3. Ex vivo expansion of hematopoietic stem cells: mission accomplished?
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Takizawa, H, primary, Schanz, U, additional, and Manz, MG, additional
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- 2011
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4. Tripokin: A multi-specific immunocytokine for cancer immunotherapy.
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Prodi E, Corbellari R, Ghezzi L, Ciambellotti S, Catastini JE, Rappuoli M, Rotta G, Sakic I, Weiss T, Weller M, Pellegrino C, Manz MG, Neri D, and De Luca R
- Abstract
Antibodies that target the tumor microenvironment can be used to deliver pro-inflammatory payloads, such as cytokines. Cytokines are small proteins able to modulate the activity of the immune system, and antibody-cytokine fusion proteins have been tested in preclinical and clinical settings. In this study, we describe Tripokin, a novel multi-specific fusion protein that combines interleukin-2 and a single amino acid mutant of tumor necrosis factor. The two pro-inflammatory payloads were fused to the L19 antibody, a clinical-grade antibody against the extradomain B of fibronectin. The human payloads were used for clinical applications, while the corresponding murine cytokines were used for preclinical studies. The resulting fusion proteins were produced in mammalian cells and purified to homogeneity. The murine Tripokin product was well tolerated in tumor-bearing mice at three doses of 30 μg in a 2-day interval and promoted rapid tumor eradication in murine models, more efficiently than single-agent immunocytokines. Tripokin induced rapid tumor necrosis and stimulated a robust immune response, impacting innate and adaptive immune pathways. In addition, the combination with immune checkpoint inhibitors further boosted the therapeutic efficacy of our molecule. Tripokin represents a promising clinical candidate for the simultaneous delivery of interleukin-2 and tumor necrosis factor to neoplastic sites., (© 2024 UICC.)
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- 2024
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5. Deciphering Factors Linked With Reduced Severe Acute Respiratory Syndrome Coronavirus 2 Susceptibility in the Swiss HIV Cohort Study.
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Abela IA, Hauser A, Schwarzmüller M, Pasin C, Kusejko K, Epp S, Cavassini M, Battegay M, Rauch A, Calmy A, Notter J, Bernasconi E, Fux CA, Leuzinger K, Perreau M, Ramette A, Gottschalk J, Schindler E, Wepf A, Marconato M, Manz MG, Frey BM, Braun DL, Huber M, Günthard HF, Trkola A, and Kouyos RD
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- Humans, Male, Female, Middle Aged, Switzerland epidemiology, Cohort Studies, Adult, Disease Susceptibility, Risk Factors, Aged, COVID-19 immunology, COVID-19 epidemiology, HIV Infections epidemiology, HIV Infections immunology, SARS-CoV-2 immunology, Antibodies, Viral blood
- Abstract
Background: Factors influencing susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain to be resolved. Using data from the Swiss HIV Cohort Study on 6270 people with human immunodeficiency virus (HIV) and serologic assessment for SARS-CoV-2 and circulating human coronavirus (HCoV) antibodies, we investigated the association of HIV-related and general parameters with SARS-CoV-2 infection., Methods: We analyzed SARS-CoV-2 polymerase chain reaction test results, COVID-19-related hospitalizations, and deaths reported to the Swiss HIV Cohort Study between 1 January 2020 and 31 December 2021. Antibodies to SARS-CoV-2 and HCoVs were determined in prepandemic (2019) and pandemic (2020) biobanked plasma samples and compared with findings in HIV-negative individuals. We applied logistic regression, conditional logistic regression, and bayesian multivariate regression to identify determinants of SARS-CoV-2 infection and antibody responses to SARS-CoV-2 in people with HIV., Results: No HIV-1-related factors were associated with SARS-CoV-2 acquisition. High prepandemic HCoV antibodies were associated with a lower risk of subsequent SARS-CoV-2 infection and with higher SARS-CoV-2 antibody responses on infection. We observed a robust protective effect of smoking on SARS-CoV-2 infection risk (adjusted odds ratio, 0.46 [95% confidence interval, .38-.56]; P < .001), which occurred even in previous smokers and was highest for heavy smokers., Conclusions: Our findings of 2 independent protective factors, smoking and HCoV antibodies, both affecting the respiratory environment, underscore the importance of the local immune milieu in regulating susceptibility to SARS-CoV-2., Competing Interests: Potential conflicts of interest . I. A. A. has received honoraria from MSD and Sanofi, a travel grant from Gilead Sciences, and a grant from Promedica Foundation. M. C.’s institution received research grants and fees for expert opinion given to Gilead, MSD and ViiV. D. L. B. reports honoraria paid to himself for advisory boards from the companies AstraZeneca, Pfizer, Gilead, MSD and ViiV. H. F. G. reports honoraria from Gilead Sciences, Merck, ViiV, GSK, Janssen, Johnson and Johnson, and Novartis for serving on data and safety monitoring and/or advisory boards; a travel grant from Gilead Sciences; and grants from the Swiss National Science Foundation (SNSF), the SHCS, the Yvonne Jacob Foundation, and the National Institutes of Health, as well as unrestricted research grants from Gilead Sciences, all paid to the author’s institution. A. T. has received honoraria from Roche Diagnostics for consultant activity; grants from the SNSF, the Swiss HIV Cohort Study, and the Pandemiefonds of the UZH Foundation; and unrestricted research grants from Gilead Sciences. R. D. K. has received grants from SNSF, the National Institutes of Health, and Gilead Sciences. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)
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- 2024
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6. An IL-7 fusion protein targeting EDA fibronectin upregulates TCF1 on CD8+ T-cells, preferentially accumulates to neoplastic lesions, and boosts PD-1 blockade.
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Di Nitto C, Ravazza D, Gilardoni E, Look T, Sun M, Prodi E, Moisoiu V, Pellegrino C, Manz MG, Puca E, Weller M, Weiss T, Neri D, and De Luca R
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- Humans, Animals, Mice, Recombinant Fusion Proteins pharmacology, Recombinant Fusion Proteins therapeutic use, Programmed Cell Death 1 Receptor antagonists & inhibitors, Programmed Cell Death 1 Receptor metabolism, Neoplasms drug therapy, Neoplasms immunology, Hepatocyte Nuclear Factor 1-alpha metabolism, Immune Checkpoint Inhibitors pharmacology, Immune Checkpoint Inhibitors therapeutic use, Up-Regulation, Female, Cell Line, Tumor, Fibronectins metabolism, Fibronectins genetics, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Interleukin-7 metabolism, Interleukin-7 pharmacology
- Abstract
Background: Anti-PD-1 antibodies have revolutionized cancer immunotherapy due to their ability to induce long-lasting complete remissions in a proportion of patients. Current research efforts are attempting to identify biomarkers and suitable combination partners to predict or further improve the activity of immune checkpoint inhibitors. Antibody-cytokine fusions are a class of pharmaceuticals that showed the potential to boost the anticancer properties of other immunotherapies. Extradomain A-fibronectin (EDA-FN), which is expressed in most solid and hematological tumors but is virtually undetectable in healthy adult tissues, is an attractive target for the delivery of cytokine at the site of the disease., Methods: In this work, we describe the generation and characterization of a novel interleukin-7-based fusion protein targeting EDA-FN termed F8(scDb)-IL7. The product consists of the F8 antibody specific to the alternatively spliced EDA of FN in the single-chain diabody (scDb) format fused to human IL-7., Results: F8(scDb)-IL7 efficiently stimulates human peripheral blood mononuclear cells in vitro. Moreover, the product significantly increases the expression of T Cell Factor 1 (TCF-1) on CD8+T cells compared with an IL2-fusion protein. TCF-1 has emerged as a pivotal transcription factor that influences the durability and potency of immune responses against tumors. In preclinical cancer models, F8(scDb)-IL7 demonstrates potent single-agent activity and eradicates sarcoma lesions when combined with anti-PD-1., Conclusions: Our results provide the rationale to explore the combination of F8(scDb)-IL7 with anti-PD-1 antibodies for the treatment of patients with cancer., Competing Interests: Competing interests: DN is a cofounder and shareholder of Philogen (www.philogen.com), a Swiss-Italian Biotech company that operates in the field of ligand-based pharmacodelivery. CDN, EProdi, RD, DR, EG and EPuca are employees of Philochem AG, a daughter company of Philogen acting as discovery unit of the group., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2024
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7. B-cell maturation antigen-directed bispecific antibodies in plasmablastic lymphoma.
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Hofer KD, Wolfensberger N, Bachofner A, Schneidawind C, Stühler C, Bühler MM, Abela IA, Müller NJ, Zenz T, Manz MG, Rösler W, Khanna N, and Schneidawind D
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- Humans, Male, Female, Aged, Middle Aged, Antineoplastic Agents, Immunological therapeutic use, Antibodies, Bispecific therapeutic use, Plasmablastic Lymphoma drug therapy, Plasmablastic Lymphoma pathology, B-Cell Maturation Antigen immunology
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- 2024
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8. IL-1 in aging and pathologies of hematopoietic stem cells.
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Caiado F and Manz MG
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- Humans, Animals, Inflammation metabolism, Inflammation pathology, Signal Transduction, Hematopoietic Stem Cells metabolism, Hematopoietic Stem Cells pathology, Aging metabolism, Interleukin-1 metabolism
- Abstract
Abstract: Defense-oriented inflammatory reactivity supports survival at younger age but might contribute to health impairments in modern, aging societies. The interleukin-1 (IL-1) cytokines are highly conserved and regulated, pleiotropic mediators of inflammation, essential to respond adequately to infection and tissue damage but also with potential host damaging effects when left unresolved. In this review, we discuss how continuous low-level IL-1 signaling contributes to aging-associated hematopoietic stem and progenitor cell (HSPC) functional impairments and how this inflammatory selective pressure acts as a driver of more profound hematological alterations, such as clonal hematopoiesis of indeterminate potential, and to overt HSPC diseases, like myeloproliferative and myelodysplastic neoplasia as well as acute myeloid leukemia. Based on this, we outline how IL-1 pathway inhibition might be used to prevent or treat inflammaging-associated HSPC pathologies., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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9. Efficacy of thrombopoietin receptor agonists versus rituximab in non-responsive immune thrombocytopenia-A single centre retrospective analysis.
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Stolz SM, Schwotzer R, Rösler W, Hofer KD, Balabanov S, Manz MG, and Rieger MJ
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Management of immune thrombocytopenia (ITP) beyond initial glucocorticoid therapy is challenging. In this retrospective single-centre cohort study, we compared all ITP patients relapsed or non-responsive to glucocorticoid therapy treated with either continuous TPO-RAs (n = 35) or rituximab induction (n = 20) between 2015 and 2022. While both groups showed high initial complete response rates (CR, 68.6 vs. 80.0%, ns), the overall rate of progression to the next therapy was higher after time-limited rituximab (75.0 vs. 42.9%), resulting in a lower relapse-free survival (median 16.6 vs. 25.8 months, log-rank; p < 0.05). We conclude that both treatments show similar initial efficacy and their ideal duration of therapy warrants further investigation., (© 2024 The Author(s). British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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10. Optimizing the Design and Geometry of T Cell-Engaging Bispecific Antibodies Targeting CEA in Colorectal Cancer.
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Elsayed A, Plüss L, Nideroest L, Rotta G, Thoma M, Zangger N, Peissert F, Pfister SK, Pellegrino C, Dakhel Plaza S, De Luca R, Manz MG, Oxenius A, Puca E, Halin C, and Neri D
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- Animals, Humans, Mice, Cell Line, Tumor, T-Lymphocytes immunology, CD3 Complex immunology, Xenograft Model Antitumor Assays, Disease Models, Animal, Antibodies, Bispecific pharmacology, Antibodies, Bispecific immunology, Colorectal Neoplasms immunology, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Carcinoembryonic Antigen immunology
- Abstract
Metastatic colorectal cancer remains a leading cause of cancer-related deaths, with a 5-year survival rate of only 15%. T cell-engaging bispecific antibodies (TCBs) represent a class of biopharmaceuticals that redirect cytotoxic T cells toward tumor cells, thereby turning immunologically "cold" tumors into "hot" ones. The carcinoembryonic antigen (CEA) is an attractive tumor-associated antigen that is overexpressed in more than 98% of patients with colorectal cancer. In this study, we report the comparison of four different TCB formats employing the antibodies F4 (targeting human CEA) and 2C11 (targeting mouse CD3ε). These formats include both antibody fragment-based and IgG-based constructs, with either one or two binding specificities of the respective antibodies. The 2 + 1 arrangement, using an anti-CEA single-chain diabody fused to an anti-CD3 single-chain variable fragment, emerged as the most potent design, showing tumor killing at subnanomolar concentrations across three different CEA+ cell lines. The in vitro activity was three times greater in C57BL/6 mouse colon adenocarcinoma cells (MC38) expressing high levels of CEA compared with those expressing low levels, highlighting the impact of CEA density in this assay. The optimal TCB candidate was tested in two different immunocompetent mouse models of colorectal cancer and showed tumor growth retardation. Ex vivo analysis of tumor infiltrates showed an increase in CD4+ and CD8+ T cells upon TCB treatment. This study suggests that bivalent tumor targeting, monovalent T-cell targeting, and a short spatial separation are promising characteristics for CEA-targeting TCBs., (©2024 American Association for Cancer Research.)
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- 2024
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11. Evaluating tixagevimab/cilgavimab prophylaxis in allogeneic haematopoietic cell transplantation recipients for COVID-19 prevention.
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Trepl J, Pasin C, Schneidawind D, Mueller NJ, Manz MG, Bankova AK, and Abela IA
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- Humans, Male, Female, Middle Aged, Adult, Retrospective Studies, Aged, Transplantation, Homologous, Pre-Exposure Prophylaxis methods, Allografts, Hematopoietic Stem Cell Transplantation adverse effects, COVID-19 prevention & control, SARS-CoV-2, Antibodies, Monoclonal, Humanized therapeutic use
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Allogeneic haematopoietic cell transplantation (allo-HCT) recipients exhibit an increased risk of COVID-19, particularly in the early post-transplant phase, due to insufficient vaccine responses. This retrospective study investigated the incidence of SARS-CoV-2 infection in allo-HCT recipients who received tixagevimab/cilgavimab pre-exposure prophylaxis (T/C PrEP) compared to those who did not. Logistic regression, adjusted for sex, age, SARS-CoV-2 vaccination status and immunosuppressive treatment, revealed a significant reduction in the likelihood of SARS-CoV-2 infection risk with T/C PrEP (adjusted odds ratio aOR = 0.26 [0.07, 0.91]). These findings suggest the potential efficacy of monoclonal antibody PrEP in protecting this vulnerable patient population from COVID-19., (© 2024 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2024
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12. A novel strategy to generate immunocytokines with activity-on-demand using small molecule inhibitors.
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Rotta G, Gilardoni E, Ravazza D, Mock J, Seehusen F, Elsayed A, Puca E, De Luca R, Pellegrino C, Look T, Weiss T, Manz MG, Halin C, Neri D, and Dakhel Plaza S
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- Humans, Immunotherapy, Cytokines, Neoplasms drug therapy
- Abstract
Cytokine-based therapeutics have been shown to mediate objective responses in certain tumor entities but suffer from insufficient selectivity, causing limiting toxicity which prevents dose escalation to therapeutically active regimens. The antibody-based delivery of cytokines significantly increases the therapeutic index of the corresponding payload but still suffers from side effects associated with peak concentrations of the product in blood upon intravenous administration. Here we devise a general strategy (named "Intra-Cork") to mask systemic cytokine activity without impacting anti-cancer efficacy. Our technology features the use of antibody-cytokine fusions, capable of selective localization at the neoplastic site, in combination with pathway-selective inhibitors of the cytokine signaling, which rapidly clear from the body. This strategy, exemplified with a tumor-targeted IL12 in combination with a JAK2 inhibitor, allowed to abrogate cytokine-driven toxicity without affecting therapeutic activity in a preclinical model of cancer. This approach is readily applicable in clinical practice., (© 2024. The Author(s).)
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- 2024
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13. Targeting the mevalonate or Wnt pathways to overcome CAR T-cell resistance in TP53-mutant AML cells.
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Mueller J, Schimmer RR, Koch C, Schneiter F, Fullin J, Lysenko V, Pellegrino C, Klemm N, Russkamp N, Myburgh R, Volta L, Theocharides AP, Kurppa KJ, Ebert BL, Schroeder T, Manz MG, and Boettcher S
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- Humans, Wnt Signaling Pathway, Immunotherapy, Adoptive, T-Lymphocytes, Tumor Suppressor Protein p53 genetics, Mevalonic Acid metabolism, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute therapy
- Abstract
TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS., (© 2024. The Author(s).)
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- 2024
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14. Historic characteristics and mortality of patients in the Swiss Amyloidosis Registry.
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Brouwers S, Heimgartner R, Laptseva N, Aguzzi A, Ehl NF, Fehr T, Hitz F, Jung HH, Kälin J, Manz MG, Müllhaupt B, Ruschitzka F, Seeger H, Stussi G, Zweier M, Flammer AJ, Gerber B, and Schwotzer R
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- Humans, Registries, Retrospective Studies, Serum Amyloid A Protein, Switzerland epidemiology, Adult, Amyloid Neuropathies, Familial diagnosis, Amyloid Neuropathies, Familial metabolism, Amyloid Neuropathies, Familial therapy, Amyloidosis
- Abstract
Aims of the Study: Systemic amyloidoses are rare protein-folding diseases with heterogeneous, often nonspecific clinical presentations. To better understand systemic amyloidoses and to apply state-of-the-art diagnostic pathways and treatment, the interdisciplinary Amyloidosis Network was founded in 2013 at University Hospital Zurich. In this respect, a registry was implemented to study the characteristics and life expectancy of patients with amyloidosis within the area covered by the network. Patient data were collected retrospectively for the period 2005-2014 and prospectively from 2015 onwards., Methods: Patients aged 18 years or older diagnosed with any subtype of systemic amyloidosis were eligible for inclusion if they were treated in one of the four referring centres (Zurich, Chur, St Gallen, Bellinzona). Baseline data were captured at the time of diagnosis. Follow-up data were assessed half-yearly for the first two years, then annually., Results: Between January 2005 and March 2020, 247 patients were screened, and 155 patients with confirmed systemic amyloidosis were included in the present analysis. The most common amyloidosis type was light-chain (49.7%, n = 77), followed by transthyretin amyloidosis (40%, n = 62) and amyloid A amyloidosis (5.2%, n = 8). Most patients (61.9%, n = 96) presented with multiorgan involvement. Nevertheless, single organ involvement was seen in all types of amyloidosis, most commonly in amyloid A amyloidosis (75%, n = 6). The median observation time of the surviving patients was calculated by the reverse Kaplan-Meier method and was 3.29 years (95% confidence interval [CI] 2.33-4.87); it was 4.87 years (95% CI 3.14-7.22) in light-chain amyloidosis patients and 1.85 years (95% CI 1.48-3.66) in transthyretin amyloidosis patients, respectively. The 1-, 3- and 5-year survival rates were 87.0% (95% CI 79.4-95.3%), 68.5% (95% CI 57.4-81.7%) and 66.0% (95% CI 54.6-79.9%) respectively for light-chain amyloidosis patients and 91.2% (95% CI 83.2-99.8%), 77.0% (95% CI 63.4-93.7%) and 50.6% (95% CI 31.8-80.3%) respectively for transthyretin amyloidosis patients. There was no significant difference between the two groups (p = 0.81)., Conclusion: During registry set-up, a more comprehensive work-up of our patients suffering mainly from light-chain amyloidosis and transthyretin amyloidosis was implemented. Survival rates were remarkably high and similar between light-chain amyloidosis and transthyretin amyloidosis, a finding which was noted in similar historic registries of international centres. However, further studies are needed to depict morbidity and mortality as the amyloidosis landscape is changing rapidly.
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- 2024
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15. Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models.
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Saito Y, Iida-Norita R, Afroj T, Refaat A, Hazama D, Komori S, Ohata S, Takai T, Oduori OS, Kotani T, Funakoshi Y, Koma YI, Murata Y, Yakushijin K, Matsuoka H, Minami H, Yokozaki H, Manz MG, and Matozaki T
- Subjects
- Humans, Mice, Animals, Rituximab pharmacology, Rituximab therapeutic use, Cell Line, Tumor, Antibodies, Immunotherapy, Disease Models, Animal, Antigens, Differentiation, Neoplasms therapy
- Abstract
Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo , we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34
+ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs., Competing Interests: TM and YM hold a patent on the antitumor drug “anti-SIRPα Ab” Japan patent number P6923942. TM has received royalties from Daiichi Sankyo. He also has received a research grant from JCR Pharmaceuticals Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Saito, Iida-Norita, Afroj, Refaat, Hazama, Komori, Ohata, Takai, Oduori, Kotani, Funakoshi, Koma, Murata, Yakushijin, Matsuoka, Minami, Yokozaki, Manz and Matozaki.)- Published
- 2023
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16. Circulating senescent myeloid cells infiltrate the brain and cause neurodegeneration in histiocytic disorders.
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Wilk CM, Cathomas F, Török O, Le Berichel J, Park MD, Bigenwald C, Heaton GR, Hamon P, Troncoso L, Scull BP, Dangoor D, Silvin A, Fleischmann R, Belabed M, Lin H, Merad Taouli E, Boettcher S, Li L, Aubry A, Manz MG, Kofler JK, Yue Z, Lira SA, Ginhoux F, Crary JF, McClain KL, Picarsic JL, Russo SJ, Allen CE, and Merad M
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- Humans, Brain metabolism, Myeloid Cells metabolism, Cell Differentiation, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf metabolism, Histiocytosis, Langerhans-Cell genetics, Histiocytosis, Langerhans-Cell pathology, Histiocytosis, Langerhans-Cell therapy
- Abstract
Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing mitogen-activated protein kinase (MAPK)-activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some individuals with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we showed that LCH-ND was caused by myeloid cells that were clonal with peripheral LCH cells. Circulating BRAFV600E
+ myeloid cells caused the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiated into senescent, inflammatory CD11a+ macrophages that accumulated in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced peripheral inflammation, brain parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent targetable mechanisms of LCH-ND., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)- Published
- 2023
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17. Twisted: Escape of epitope-edited healthy cells from immune attack.
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Volta L and Manz MG
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- Epitopes, Cell Membrane, Hematopoietic Stem Cells, Immunotherapy
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Hematopoietic stem and progenitor cell-derived neoplasia is challenging to target by cell surface-directed immunotherapy due to lack of tumor cell-specific antigen identification. Marone et al. (2023. J. Exp. Med.https://doi.org/10.1084/jem.20231235) provide a solution by target-epitope resistance editing in healthy hematopoietic stem cells., (© 2023 Volta and Manz.)
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- 2023
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18. Intrapatient competition of VEXAS syndrome and CML clones.
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Djerbi N, Zimmermann K, Roncador M, Becker MO, Manz MG, and Balabanov S
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- Humans, Leukemia, Myelogenous, Chronic, BCR-ABL Positive complications, Myelodysplastic Syndromes complications, Skin Diseases, Genetic complications
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- 2023
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19. Prognostic Significance of Measurable Residual Disease Detection by Flow Cytometry in Autologous Stem Cell Apheresis Products in AML.
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Tettero JM, Buisman Y, Ngai LL, Bachas C, Gjertsen BT, Kelder A, van de Loosdrecht AA, Manz MG, Pabst T, Scholten W, Ossenkoppele GJ, Cloos J, and de Leeuw DC
- Abstract
Competing Interests: BTG serves as a consultant for BerGenBio, Phizer, Inc, and Novartis and holds stock options in Alden Cancer Therapy and KinN Therapeutics. MGM serves as a consultant for CDR-Life, Inc; holds stock options in CDR-Life, Inc; and has a patent licensed to the University of Zurich. GJO serves as a consultant for Novartis, Pfizer, Inc, Celgene, Janssen, Agios, Amgen, Gilead, Astellas, Roche, Jazz Pharmaceuticals, and Merus; has received honoraria from Novartis, Celgene, Agios, Gilead, and Astellas; received research funding from Novartis; and holds a membership on an entity’s Board of Directors for Roche. JC has received research funding from Takeda, DC-One, Genentech, Janssen, Novartis, and Merus. All the other authors have no conflicts of interest to disclose.
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- 2023
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20. Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma.
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Hänsch L, Peipp M, Mastall M, Villars D, Myburgh R, Silginer M, Weiss T, Gramatzki D, Vasella F, Manz MG, Weller M, and Roth P
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- Mice, Animals, Humans, T-Lymphocytes, Cell Line, Tumor, Immunotherapy, Adoptive methods, Xenograft Model Antitumor Assays, Receptors, Chimeric Antigen genetics, Glioblastoma pathology, Glioma pathology
- Abstract
Background: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors., Methods: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models., Results: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals., Conclusions: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)
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- 2023
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21. Circulating senescent myeloid cells drive blood brain barrier breakdown and neurodegeneration.
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Wilk CM, Cathomas F, Török O, Le Berichel J, Park MD, Heaton GR, Hamon P, Troncoso L, Scull BP, Dangoor D, Silvin A, Fleischmann R, Belabed M, Lin H, Taouli EM, Boettcher S, Manz MG, Kofler JK, Yue Z, Lira SA, Ginhoux F, Crary JF, McClain KL, Picarsic JL, Russo SJ, Allen CE, and Merad M
- Abstract
Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAF V600E
+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a+ macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND.- Published
- 2023
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22. Haploidentical transplant with posttransplant cyclophosphamide vs matched related and unrelated donor transplant in acute myeloid leukemia and myelodysplastic neoplasm.
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Rieger MJ, Stolz SM, Müller AM, Schwotzer R, Nair G, Schneidawind D, Manz MG, and Schanz U
- Abstract
Hematopoietic cell transplantation from haploidentical donors (haploHCT) has facilitated treatment of AML and MDS by increasing donor availability and became more feasible since the introduction of post-transplant cyclophosphamide (ptCY). In our single-center retrospective analysis including 213 patients with AML or MDS, we compare the outcome of haploHCT (n = 40) with ptCY with HCT from HLA-identical MRD (n = 105) and MUD (n = 68). At 2 years after transplantation, overall survival (OS) after haploHCT was not significantly different (0.59; 95% confidence interval 0.44-0.79) compared to MRD (0.77; 0.67-0.88) and MUD transplantation (0.72; 0.64-0.82, p = 0.51). While progression-free survival (PFS) was also not significantly different (haploHCT: 0.60; 0.46-0.78, MRD: 0.55; 0.44-0.69, MUD: 0.64; 0.55-0.74, p = 0.64), non-relapse mortality (NRM) was significantly higher after haploHCT (0.18; 0.08-0.33) vs. MRD (0.029; 0.005-0.09) and MUD (0.06; 0.02-0.12, p < 0.05). Higher NRM was mainly caused by a higher rate of fatal infections, while deaths related to GvHD or other non-relapse reasons were rare in all groups. As most fatal infections occurred early and were bacterial related, one potential risk factor among many was identified in the significantly longer time to neutrophil engraftment after haploHCT with a median of 16 days (interquartile range; 14.8-20.0) vs. 12 days (10.0-13.0) for MRD and 11 days (10.0-13.0) for MUD (p = 0.01)., (© 2023. The Author(s).)
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- 2023
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23. Complication rates of peripherally inserted central catheters vs implanted ports in patients receiving systemic anticancer therapy: A retrospective cohort study.
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Rieger MJ, Schenkel X, Dedic I, Brunn T, Gnannt R, Hofmann M, de Rougemont O, Stolz SM, Rösler W, Studt JD, Balabanov S, Wicki A, Lorch A, Manz MG, and Schwotzer R
- Subjects
- Humans, Retrospective Studies, Risk Factors, Catheterization, Central Venous adverse effects, Central Venous Catheters adverse effects, Catheter-Related Infections epidemiology, Catheter-Related Infections etiology, Neoplasms drug therapy, Neoplasms complications
- Abstract
While implanted port catheters ("PORTs") have historically been the standard device for intravenous systemic anticancer therapy, the use of peripherally inserted central catheters (PICCs) has increased continuously and reliable catheter selection guidelines are lacking. We compare complication rates of PORTs and PICCs in cancer treatment in a retrospective study of 3365 patients with both solid organ (n = 2612) and hematologic (n = 753) malignancies, between 2001 and 2021. 26.4% (n = 890) of all patients were treated via PICCs and 73.6% (2475) via PORTs. 20.7% (578) experienced a major catheter-related complication with a higher rate in PICCs than in PORTs (23.5% vs 14.9%, P < .001). Among major complications, infections and mechanical complications were more common in PICCs than in PORTs (11.9% vs 6.4%, P = .001, 7.3% vs 4.2%, P = .002), whereas the rate of thrombosis was similar (3.4% vs 3.0%, P = .9). While PORTs had a higher rate of periprocedural complications (2.7% vs 1.1%, P < .05), PICCs overall complication rate exceeded PORTs within 3 days from implantation. Median follow-up was 49 (PICC) and 60 weeks (PORT). PORTs are safer and therefore should be preferred in this setting regardless of catheter dwell time., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
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- 2023
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24. Measurable residual disease-guided therapy in intermediate-risk acute myeloid leukemia patients is a valuable strategy in reducing allogeneic transplantation without negatively affecting survival.
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Tettero JM, Ngai LL, Bachas C, Breems DA, Fischer T, Gjertsen BT, Gradowska P, Griskevicius L, Janssen JJWM, Juliusson G, Maertens J, Manz MG, Pabst T, Passweg J, Porkka K, Valk PJM, Löwenberg B, Ossenkoppele GJ, and Cloos J
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- Humans, Transplantation, Homologous, Neoplasm, Residual, Recurrence, Transplantation Conditioning, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy
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- 2023
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25. Erratum: Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells.
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Magnani CF, Myburgh R, Brunn S, Chambovey M, Ponzo M, Volta L, Manfredi F, Pellegrino C, Pascolo S, Miskey C, Sandoval-Villegas N, Ivics Z, Shizuru JA, Neri D, and Manz MG
- Abstract
[This corrects the article DOI: 10.1016/j.omto.2023.07.003.]., (© 2023 The Author(s).)
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- 2023
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26. Anti-CD117 CAR T cells incorporating a safety switch eradicate human acute myeloid leukemia and hematopoietic stem cells.
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Magnani CF, Myburgh R, Brunn S, Chambovey M, Ponzo M, Volta L, Manfredi F, Pellegrino C, Pascolo S, Miskey C, Ivics Z, Shizuru JA, Neri D, and Manz MG
- Abstract
Discrimination between hematopoietic stem cells and leukemic stem cells remains a major challenge for acute myeloid leukemia immunotherapy. CAR T cells specific for the CD117 antigen can deplete malignant and healthy hematopoietic stem cells before consolidation with allogeneic hematopoietic stem cell transplantation in absence of cytotoxic conditioning. Here we exploit non-viral technology to achieve early termination of CAR T cell activity to prevent incoming graft rejection. Transient expression of an anti-CD117 CAR by mRNA conferred T cells the ability to eliminate CD117+ targets in vitro and in vivo . As an alternative approach, we used a Sleeping Beauty transposon vector for the generation of CAR T cells incorporating an inducible Caspase 9 safety switch. Stable CAR expression was associated with high proportion of T memory stem cells, low levels of exhaustion markers, and potent cellular cytotoxicity. Anti-CD117 CAR T cells mediated depletion of leukemic cells and healthy hematopoietic stem cells in NSG mice reconstituted with human leukemia or CD34+ cord blood cells, respectively, and could be terminated in vivo . The use of a non-viral technology to control CAR T cell pharmacokinetic properties is attractive for a first-in-human study in patients with acute myeloid leukemia prior to hematopoietic stem cell transplantation., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)
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- 2023
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27. Age and sex associate with outcome in older AML and high risk MDS patients treated with 10-day decitabine.
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Hilberink JR, van Zeventer IA, Chitu DA, Pabst T, Klein SK, Stussi G, Griskevicius L, Valk PJM, Cloos J, van de Loosdrecht AA, Breems D, van Lammeren-Venema D, Boersma R, Jongen-Lavrencic M, Fehr M, Hoogendoorn M, Manz MG, Söhne M, van Marwijk Kooy R, Deeren D, van der Poel MWM, Legdeur MC, Tick L, Chalandon Y, Ammatuna E, Blum S, Löwenberg B, Ossenkoppele GJ, and Huls G
- Subjects
- Humans, Male, Female, Aged, Decitabine therapeutic use, Mutation, Treatment Outcome, Myelodysplastic Syndromes genetics, Leukemia, Myeloid, Acute genetics
- Abstract
Treatment choice according to the individual conditions remains challenging, particularly in older patients with acute myeloid leukemia (AML) and high risk myelodysplastic syndrome (MDS). The impact of performance status, comorbidities, and physical functioning on survival is not well defined for patients treated with hypomethylating agents. Here we describe the impact of performance status (14% ECOG performance status 2), comorbidity (40% HCT-comorbidity index ≥ 2), and physical functioning (41% short physical performance battery < 9 and 17% ADL index < 6) on overall survival (OS) in 115 older patients (age ≥ 66 years) treated on a clinical trial with a 10-day decitabine schedule. None of the patient-related variables showed a significant association with OS. Multivariable analysis revealed that age > 76 years was significantly associated with reduced OS (HR 1.58; p = 0.043) and female sex was associated with superior OS (HR 0.62; p = 0.06). We further compared the genetic profiles of these subgroups. This revealed comparable mutational profiles in patients younger and older than 76 years, but, interestingly, revealed significantly more prevalent mutated ASXL1, STAG2, and U2AF1 in male compared to female patients. In this cohort of older patients treated with decitabine age and sex, but not comorbidities, physical functioning or cytogenetic risk were associated with overall survival., (© 2023. The Author(s).)
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- 2023
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28. Blocking the CD47-SIRPα interaction reverses the disease phenotype in a polycythemia vera mouse model.
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Lysenko V, Schürch PM, Tuzlak S, van Wijk NW, Kovtonyuk LV, Becher B, Manz MG, Kreutmair S, and Theocharides APA
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- Animals, Mice, CD47 Antigen metabolism, Disease Models, Animal, Macrophages, Monocytes metabolism, Phagocytosis, Phenotype, Polycythemia Vera genetics, Polycythemia Vera metabolism
- Abstract
Polycythemia vera (PV) is a hematopoietic stem cell neoplasm driven by somatic mutations in JAK2, leading to increased red blood cell (RBC) production uncoupled from mechanisms that regulate physiological erythropoiesis. At steady-state, bone marrow macrophages promote erythroid maturation, whereas splenic macrophages phagocytose aged or damaged RBCs. The binding of the anti-phagocytic ("don't eat me") CD47 ligand expressed on RBCs to the SIRPα receptor on macrophages inhibits phagocytic activity protecting RBCs from phagocytosis. In this study, we explore the role of the CD47-SIRPα interaction on the PV RBC life cycle. Our results show that blocking CD47-SIRPα in a PV mouse model due to either anti-CD47 treatment or loss of the inhibitory SIRPα-signal corrects the polycythemia phenotype. Anti-CD47 treatment marginally impacted PV RBC production while not influencing erythroid maturation. However, upon anti-CD47 treatment, high-parametric single-cell cytometry identified an increase of MerTK+ splenic monocyte-derived effector cells, which differentiate from Ly6C
hi monocytes during inflammatory conditions, acquire an inflammatory phagocytic state. Furthermore, in vitro, functional assays showed that splenic JAK2 mutant macrophages were more "pro-phagocytic," suggesting that PV RBCs exploit the CD47-SIRPα interaction to escape innate immune attacks by clonal JAK2 mutant macrophages., (© 2023. The Author(s).)- Published
- 2023
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29. Prospective validation of the prognostic relevance of CD34+CD38- AML stem cell frequency in the HOVON-SAKK132 trial.
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Ngai LL, Hanekamp D, Janssen F, Carbaat-Ham J, Hofland MAMA, Fayed MMHE, Kelder A, Oudshoorn-van Marsbergen L, Scholten WJ, Snel AN, Bachas C, Tettero JM, Breems DA, Fischer T, Gjertsen BT, Griškevičius L, Juliusson G, van de Loosdrecht AA, Maertens JA, Manz MG, Pabst T, Passweg JR, Porkka K, Valk PJM, Gradowska P, Löwenberg B, de Leeuw DC, Janssen JJWM, Ossenkoppele GJ, and Cloos J
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- Humans, Prognosis, Antigens, CD34, ADP-ribosyl Cyclase 1, Stem Cells, Neoplastic Stem Cells, Flow Cytometry, Leukemia, Myeloid, Acute
- Published
- 2023
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30. Ex vivo drug response heterogeneity reveals personalized therapeutic strategies for patients with multiple myeloma.
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Kropivsek K, Kachel P, Goetze S, Wegmann R, Festl Y, Severin Y, Hale BD, Mena J, van Drogen A, Dietliker N, Tchinda J, Wollscheid B, Manz MG, and Snijder B
- Subjects
- Humans, Plasma Cells pathology, Proteasome Inhibitors therapeutic use, Bone Marrow pathology, Immunotherapy, Multiple Myeloma drug therapy, Multiple Myeloma genetics, Multiple Myeloma pathology
- Abstract
Multiple myeloma (MM) is a plasma cell malignancy defined by complex genetics and extensive patient heterogeneity. Despite a growing arsenal of approved therapies, MM remains incurable and in need of guidelines to identify effective personalized treatments. Here, we survey the ex vivo drug and immunotherapy sensitivities across 101 bone marrow samples from 70 patients with MM using multiplexed immunofluorescence, automated microscopy and deep-learning-based single-cell phenotyping. Combined with sample-matched genetics, proteotyping and cytokine profiling, we map the molecular regulatory network of drug sensitivity, implicating the DNA repair pathway and EYA3 expression in proteasome inhibitor sensitivity and major histocompatibility complex class II expression in the response to elotuzumab. Globally, ex vivo drug sensitivity associated with bone marrow microenvironmental signatures reflecting treatment stage, clonality and inflammation. Furthermore, ex vivo drug sensitivity significantly stratified clinical treatment responses, including to immunotherapy. Taken together, our study provides molecular and actionable insights into diverse treatment strategies for patients with MM., (© 2023. The Author(s).)
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- 2023
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31. Indications and Outcomes of Patients Receiving Therapeutic Plasma Exchange under Critical Care Conditions: A Retrospective Eleven-Year Single-Center Study at a Tertiary Care Center.
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Ring A, Sieber WA, Studt JD, Schuepbach RA, Ganter CC, Manz MG, Müller AMS, and David S
- Abstract
Background: Therapeutic plasma exchange (TPE) is frequently performed in critical care settings for heterogenous indications. However, specific intensive care unit (ICU) data regarding TPE indications, patient characteristics and technical details are sparse. Methods : We performed a retrospective, single-center study using data from January 2010 until August 2021 for patients treated with TPE in an ICU setting at the University Hospital Zurich. Data collected included patient characteristics and outcomes, ICU-specific parameters, as well as apheresis-specific technical parameters and complications. Results : We identified n = 105 patients receiving n = 408 TPEs for n = 24 indications during the study period. The most common was thrombotic microangiopathies (TMA) (38%), transplant-associated complications (16.3%) and vasculitis (14%). One-third of indications (35.2%) could not be classified according to ASFA. Anaphylaxis was the most common TPE-related complication (6.7%), while bleeding complications were rare (1%). The median duration of ICU stay was 8 ± 14 days. Ventilator support, renal replacement therapy or vasopressors were required in 59 (56.2%), 26 (24.8%), and 35 (33.3%) patients, respectively, and 6 (5.7%) patients required extracorporeal membrane oxygenation. The overall hospital survival rate was 88.6%. Conclusion : Our study provides valuable real-world data on heterogenous TPE indications for patients in the ICU setting, potentially supporting decision-making.
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- 2023
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32. Antibody response to a third SARS-CoV-2 vaccine dose in recipients of an allogeneic haematopoietic cell transplantation.
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Bankova AK, Pasin C, Huang A, Cicin-Sain C, Epp S, Audige A, Mueller NJ, Nilsson J, Vilinovszki O, Nair G, Wolfensberger N, Hockl P, Schanz U, Trkola A, Kouyos R, Hasse B, Zinkernagel AS, Manz MG, Abela IA, and Müller AMS
- Subjects
- Humans, COVID-19 Vaccines, Antibody Formation, SARS-CoV-2, Transplant Recipients, Vaccination, Antibodies, Viral, COVID-19 prevention & control, Hematopoietic Stem Cell Transplantation
- Abstract
Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)
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- 2023
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33. Aging drives Tet2+/- clonal hematopoiesis via IL-1 signaling.
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Caiado F, Kovtonyuk LV, Gonullu NG, Fullin J, Boettcher S, and Manz MG
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- Mice, Animals, Clonal Hematopoiesis, Hematopoiesis genetics, Aging genetics, Interleukin-1 genetics, Mutation, DNA-Binding Proteins genetics, Cardiovascular Diseases etiology, Dioxygenases genetics
- Abstract
Clonal hematopoiesis of indeterminate potential (CHIP), also referred to as aging-related clonal hematopoiesis, is defined as an asymptomatic clonal expansion of mutant mature hematopoietic cells in ≥4% of blood leukocytes. CHIP associates with advanced age and increased risk for hematological malignancy, cardiovascular disease, and all-cause mortality. Loss-of-function somatic mutations in TET2 are frequent drivers of CHIP. However, the contribution of aging-associated cooperating cell-extrinsic drivers, like inflammation, remains underexplored. Using bone marrow (BM) transplantation and newly developed genetic mosaicism (HSC-SCL-Cre-ERT; Tet2+/flox; R26+/tm6[CAG-ZsGreen1]Hze) mouse models of Tet2+/-driven CHIP, we observed an association between increased Tet2+/- clonal expansion and higher BM levels of the inflammatory cytokine interleukin-1 (IL-1) upon aging. Administration of IL-1 to mice carrying CHIP led to an IL-1 receptor 1 (IL-1R1)-dependent expansion of Tet2+/- hematopoietic stem and progenitor cells (HSPCs) and mature blood cells. This expansion was caused by increased Tet2+/- HSPC cell cycle progression, increased multilineage differentiation, and higher repopulation capacity compared with their wild-type counterparts. In agreement, IL-1α-treated Tet2+/- hematopoietic stem cells showed increased DNA replication and repair transcriptomic signatures and reduced susceptibility to IL-1α-mediated downregulation of self-renewal genes. More important, genetic deletion of IL-1R1 in Tet2+/- HPSCs or pharmacologic inhibition of IL-1 signaling impaired Tet2+/- clonal expansion, establishing the IL-1 pathway as a relevant and therapeutically targetable driver of Tet2+/- CHIP progression during aging., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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34. BRAF inhibitor treatment of classical hairy cell leukemia allows successful vaccination against SARS-CoV-2.
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Konrat J, Rösler W, Roiss M, Meier-Abt F, Widmer CC, Balabanov S, Manz MG, and Zenz T
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- Humans, SARS-CoV-2, Vemurafenib therapeutic use, Proto-Oncogene Proteins B-raf, COVID-19 Vaccines, Pandemics, Protein Kinase Inhibitors, Vaccination, Antibodies, Viral, COVID-19 prevention & control, Leukemia, Hairy Cell drug therapy
- Abstract
In classical hairy cell leukemia (HCL), standard treatments including purine analogs achieve a durable response (up to 90%), but lead to severe immunosuppression and long-lasting depletion of CD4 + T lymphocytes. The BRAF inhibitor vemurafenib is effective in HCL, but its use in first-line treatment is restricted to select clinical situations (e.g. active infection). Its impact on immune function or response to vaccines in HCL is unclear. We treated four HCL patients with vemurafenib during the COVID-19 pandemic and monitored immune reconstitution and response to SARS-CoV-2 immunization. All patients responded to HCL treatment with normalization of peripheral blood counts. No severe infections occurred. As an indication of limited immunosuppression by vemurafenib, stable CD4 + and CD8 + T lymphocyte counts and immunoglobulin levels were observed. Three out of four patients received SARS-CoV-2 vaccination (Pfizer-BioNTech) during treatment with vemurafenib. IgG antibody levels against the spike-protein of SARS-CoV-2 were detected (40-818 AE/ml). Our data suggest that vemurafenib has limited effects on cellular and humoral immune function in HCL, which allows for successful SARS-CoV-2 vaccination. These data support the use of BRAF inhibitors during the current pandemic where continued immune response is necessary for minimizing the COVID-19-related risk of non-vaccinated patients., (© 2022. The Author(s).)
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- 2023
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35. Prognostic Value of FLT3 -Internal Tandem Duplication Residual Disease in Acute Myeloid Leukemia.
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Grob T, Sanders MA, Vonk CM, Kavelaars FG, Rijken M, Hanekamp DW, Gradowska PL, Cloos J, Fløisand Y, van Marwijk Kooy M, Manz MG, Ossenkoppele GJ, Tick LW, Havelange V, Löwenberg B, Jongen-Lavrencic M, and Valk PJM
- Subjects
- Humans, Prognosis, Mutation, Recurrence, Neoplasm, Residual genetics, Nuclear Proteins genetics, fms-Like Tyrosine Kinase 3 genetics, Leukemia, Myeloid, Acute drug therapy
- Abstract
Purpose: The applicability of FLT3 -internal tandem duplications ( FLT3 -ITD) for assessing measurable residual disease (MRD) in acute myeloid leukemia (AML) in complete remission (CR) has been hampered by patient-specific duplications and potential instability of FLT3 -ITD during relapse. Here, we comprehensively investigated the impact of next-generation sequencing (NGS)-based FLT3 -ITD MRD detection on treatment outcome in a cohort of patients with newly diagnosed AML in relation to established prognostic factors at diagnosis and other MRD measurements, ie, mutant NPM1 and multiparameter flow cytometry., Methods: In 161 patients with de novo FLT3 -ITD AML, NGS was performed at diagnosis and in CR after intensive remission induction treatment. FLT3 -ITD MRD status was correlated with the cumulative incidence of relapse and overall survival (OS)., Results: NGS-based FLT3 -ITD MRD was present in 47 of 161 (29%) patients with AML. Presence of FLT3 -ITD MRD was associated with increased risk of relapse (4-year cumulative incidence of relapse, 75% FLT3 -ITD MRD v 33% no FLT3 -ITD MRD; P < .001) and inferior OS (4-year OS, 31% FLT3 -ITD MRD v 57% no FLT3 -ITD MRD; P < .001). In multivariate analysis, detection of FLT3 -ITD MRD in CR confers independent prognostic significance for relapse (hazard ratio, 3.55; P < .001) and OS (hazard ratio 2.51; P = .002). Strikingly, FLT3 -ITD MRD exceeds the prognostic value of most generally accepted clinical and molecular prognostic factors, including the FLT3 -ITD allelic ratio at diagnosis and MRD assessment by NGS-based mutant NPM1 detection or multiparameter flow cytometry., Conclusion: NGS-based detection of FLT3 -ITD MRD in CR identifies patients with AML with profound risk of relapse and death that outcompetes the significance of most established prognostic factors at diagnosis and during therapy, and furnishes support for FLT3 -ITD as a clinically relevant biomarker for dynamic disease risk assessment in AML.
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- 2023
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36. Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics.
- Author
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Lucaroni L, Georgiev T, Prodi E, Puglioli S, Pellegrino C, Favalli N, Prati L, Manz MG, Cazzamalli S, Neri D, Oehler S, and Bassi G
- Subjects
- Male, Humans, Dipeptides therapeutic use, Prostate-Specific Antigen, Glutamate Carboxypeptidase II metabolism, Antigens, Surface metabolism, Radioisotopes therapeutic use, Salivary Glands diagnostic imaging, Salivary Glands metabolism, Kidney metabolism, Lutetium therapeutic use, Radiopharmaceuticals therapeutic use, Prostatic Neoplasms, Castration-Resistant metabolism
- Abstract
Purpose: Recently, Pluvicto™ ([
177 Lu]Lu-PSMA-617), a small-molecule prostate-specific membrane antigen (PSMA) radioligand therapeutic, has been approved by the FDA in metastatic castration-resistant prostate cancer. Pluvicto™ and other PSMA-targeting radioligand therapeutics (RLTs) have shown side effects due to accumulation in certain healthy tissues, such as salivary glands and kidney. Until now, the molecular mechanism underlying the undesired accumulation of PSMA-targeting RLTs had not been elucidated., Methods: We compared the sequence of PSMA with the entire human proteome to identify proteins closely related to the target. We have identified glutamate carboxypeptidase III (GCPIII), N-acetylated alpha-linked acidic dipeptidase like 1 (NAALADL-1), and transferrin receptor 1 (TfR1) as extracellular targets with the highest similarity to PSMA. The affinity of compound 1 for PSMA, GCPIII, NAALADL-1, and TfR1 was measured by fluorescence polarization. The expression of the putative anti-target GCPIII was assessed by immunofluorescence on human salivary glands and kidney, using commercially available antibodies., Results: A fluorescent derivative of Pluvicto™ (compound 1) bound tightly to PSMA and to GCPIII in fluorescence polarization experiments, while no interaction was observed with NAALADL-1 and TfR1. Immunofluorescence analysis revealed abundant expression of GCPIII both in healthy human kidney and salivary glands., Conclusion: We conclude that the membranous expression of GCPIII in kidney and salivary gland may be the underlying cause for unwanted accumulation of Pluvicto™ and other Glu-ureido PSMA radio pharmaceuticals in patients., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)- Published
- 2023
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37. Generation of a novel fully human non-superagonistic anti-CD28 antibody with efficient and safe T-cell co-stimulation properties.
- Author
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Elsayed A, Pellegrino C, Plüss L, Peissert F, Benz R, Ulrich F, Thorhallsdottir G, Plaza SD, Villa A, Mock J, Puca E, De Luca R, Manz MG, Halin C, and Neri D
- Subjects
- Humans, Mice, Animals, CD28 Antigens, Receptors, Antigen, T-Cell metabolism, Epitopes metabolism, Lymphocyte Activation, CD3 Complex, Leukocytes, Mononuclear metabolism, T-Lymphocytes
- Abstract
Antibody-based therapeutics represent an important class of biopharmaceuticals in cancer immunotherapy. CD3 bispecific T-cell engagers activate cytotoxic T-cells and have shown remarkable clinical outcomes against several hematological malignancies. The absence of a costimulatory signal through CD28 typically leads to insufficient T-cell activation and early exhaustion. The combination of CD3 and CD28 targeting products offers an attractive strategy to boost T-cell activity. However, the development of CD28-targeting therapies ceased after TeGenero's Phase 1 trial in 2006 evaluating a superagonistic anti-CD28 antibody (TGN1412) resulted in severe life-threatening side effects. Here, we describe the generation of a novel fully human anti-CD28 antibody termed "E1P2" using phage display technology. E1P2 bound to human and mouse CD28 as shown by flow cytometry on primary human and mouse T-cells. Epitope mapping revealed a conformational binding epitope for E1P2 close to the apex of CD28, similar to its natural ligand and unlike the lateral epitope of TGN1412. E1P2, in contrast to TGN1412, showed no signs of in vitro superagonistic properties on human peripheral blood mononuclear cells (PBMCs) using different healthy donors. Importantly, an in vivo safety study in humanized NSG mice using E1P2, in direct comparison and contrast to TGN1412, did not cause cytokine release syndrome. In an in vitro activity assay using human PBMCs, the combination of E1P2 with CD3 bispecific antibodies enhanced tumor cell killing and T-cell proliferation. Collectively, these data demonstrate the therapeutic potential of E1P2 to improve the activity of T-cell receptor/CD3 activating constructs in targeted immunotherapeutic approaches against cancer or infectious diseases.
- Published
- 2023
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38. Diabetes insipidus and Guillain-Barré-like syndrome following CAR-T cell therapy: a case report.
- Author
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Koch C, Fleischer J, Popov T, Frontzek K, Schreiner B, Roth P, Manz MG, Unseld S, Müller AMS, and Russkamp NF
- Subjects
- Humans, Immunotherapy, Adoptive adverse effects, Cell- and Tissue-Based Therapy, Receptors, Chimeric Antigen, Lymphoma, Non-Hodgkin, Central Nervous System Neoplasms, Diabetes Insipidus etiology, Diabetes Mellitus
- Abstract
Background: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common adverse event of CD19-directed chimeric antigen receptor (CAR) T cell therapy. Other neurological adverse events, however, have not methodically been described and studied. Furthermore, safety data on CAR-T cell therapy in patients with central nervous system (CNS) lymphoma remain limited., Main Body: We here report occurrence of a Guillain-Barré-like syndrome (GBS) and central diabetes insipidus (cDI) following tisagenlecleucel therapy for relapsed high-grade lymphoma with CNS involvement. Both complications were refractory to standard treatment of ICANS. Weakness of respiratory muscles required mechanical ventilation and tracheostomy while cDI was treated with desmopressin substitution for several weeks. Muscle-nerve biopsy and nerve conduction studies confirmed an axonal pattern of nerve damage. T cell-rich infiltrates and detection of the CAR transgene in muscle-nerve sections imply a direct or indirect role of CAR-T cell-mediated inflammation. In line with current treatment guidelines for GBS, intravenous immunoglobulin was administered and gradual but incomplete recovery was observed over the course of several months., Conclusions: This case report highlights the risk of rare but severe neurological adverse events, such as acute GBS or cDI, in patients treated with CAR-T cells. It further underlines the importance of appropriate patient surveillance and systematic reporting of rare complications to eventually improve treatment., Competing Interests: Competing interests: AMSM received honoraria for advisory boards, consulting, and lectures/talks from Novartis, Gilead Sciences, Bristol Myers Squibb, and Janssen., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2023
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39. Fulminant Cardiotoxicity in a Patient With Cardiac Lymphoma Treated With CAR-T Cells.
- Author
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Koch C, Montrasio G, Scherr BF, Schimmer R, Matter CM, Bühler KP, Manz MG, and Müller AMS
- Abstract
Competing Interests: Dr Müller has received honoraria for advisory boards, consulting, and lectures/talks from Novartis, Gilead Sciences, Bristol Myers Squibb, and Janssen. Dr Matter has received consulting or speaker honoraria from Amgen and Novartis; and grants to the institution from Eli Lilly, AstraZeneca, Novartis, MSD, the Swiss National Science Foundation, and the Swiss Heart Foundation. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Published
- 2022
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40. Concordance in measurable residual disease result after first and second induction cycle in acute myeloid leukemia: An outcome- and cost-analysis.
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Tettero JM, Al-Badri WKW, Ngai LL, Bachas C, Breems DA, van Elssen CHMJ, Fischer T, Gjertsen BT, van Gorkom GNY, Gradowska P, Greuter MJE, Griskevicius L, Juliusson G, Maertens J, Manz MG, Pabst T, Passweg J, Porkka K, Löwenberg B, Ossenkoppele GJ, Janssen JJWM, and Cloos J
- Abstract
Measurable residual disease (MRD) measured using multiparameter flow-cytometry (MFC) has proven to be an important prognostic biomarker in acute myeloid leukemia (AML). In addition, MRD is increasingly used to guide consolidation treatment towards a non-allogenic stem cell transplantation treatment for MRD-negative patients in the ELN-2017 intermediate risk group. Currently, measurement of MFC-MRD in bone marrow is used for clinical decision making after 2 cycles of induction chemotherapy. However, measurement after 1 cycle has also been shown to have prognostic value, so the optimal time point remains a question of debate. We assessed the independent prognostic value of MRD results at either time point and concordance between these for 273 AML patients treated within and according to the HOVON-SAKK 92, 102, 103 and 132 trials. Cumulative incidence of relapse, event free survival and overall survival were significantly better for MRD-negative (<0.1%) patients compared to MRD-positive patients after cycle 1 and cycle 2 ( p ≤ 0.002, for all comparisons). A total of 196 patients (71.8%) were MRD-negative after cycle 1, of which the vast majority remained negative after cycle 2 (180 patients; 91.8%). In contrast, of the 77 MRD-positive patients after cycle 1, only 41 patients (53.2%) remained positive. A cost reduction of -€571,751 per 100 patients could be achieved by initiating the donor search based on the MRD-result after cycle 1. This equals to a 50.7% cost reduction compared to the current care strategy in which the donor search is initiated for all patients. These results show that MRD after cycle 1 has prognostic value and is highly concordant with MRD status after cycle 2. When MRD-MFC is used to guide consolidation treatment (allo vs non-allo) in intermediate risk patients, allogeneic donor search may be postponed or omitted after cycle 1. Since the majority of MRD-negative patients remain negative after cycle 2, this could safely reduce the number of allogeneic donor searches and reduce costs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tettero, Al-Badri, Ngai, Bachas, Breems, van Elssen, Fischer, Gjertsen, van Gorkom, Gradowska, Greuter, Griskevicius, Juliusson, Maertens, Manz, Pabst, Passweg, Porkka, Löwenberg, Ossenkoppele, Janssen and Cloos.)
- Published
- 2022
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41. TLR1/2-stimulated DCs "prime" HSCs via IL-1β.
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Caiado F and Manz MG
- Subjects
- Cytokines, Interleukin-1beta, Dendritic Cells, Toll-Like Receptor 1
- Published
- 2022
- Full Text
- View/download PDF
42. Addition of romiplostim to conditioning prior to HSCT allows chemotherapy reduction while maintaining engraftment levels.
- Author
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Wilk CM, Kovtonyuk LV, and Manz MG
- Subjects
- Animals, Mice, Receptors, Fc, Recombinant Fusion Proteins, Thrombopoietin pharmacology, Thrombopoietin therapeutic use, Transplantation Conditioning, Busulfan, Hematopoietic Stem Cell Transplantation
- Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment approach for certain benign and malignant hematologic diseases. The actual HSCT is preceded by a conditioning therapy that reduces host-vs-HSCT graft rejection and creates niche space for transplanted hematopoietic stem and progenitor cells (HSPCs). Conditioning consists of chemotherapy with or without irradiation and is a major cause of side effects in HSCT. However, reduction of the intensity of cytotoxic conditioning leads to higher rates of engraftment failure and increased rates of relapse. We here tested if the addition of an HSC cycling inducing agent during conditioning allows to diminish the dose of conditioning drugs without reducing subsequent transplanted HSC engraftment in a mouse HSCT model. The thrombopoietin receptor agonist romiplostim was shown to induce cell cycling activity in hematopoietic stem cells (HSCs). We thus tested if the addition of romiplostim to the clinically applied conditioning chemotherapy regimen cyclophosphamide and busulfan leads to increased efficacy of the chemotherapeutic regimen. We found that romiplostim not only sensitizes HSCs to chemotherapy but also enables a reduction of the main chemotherapeutic component busulfan by half while HSC engraftment levels are maintained in long-term, serial transplantation assays., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
43. Comprehensive Validation of Diagnostic Next-Generation Sequencing Panels for Acute Myeloid Leukemia Patients.
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Wagner U, Wong C, Camenisch U, Zimmermann K, Rechsteiner M, Valtcheva N, Theocharides A, Widmer CC, Manz MG, Moch H, Wild PJ, and Balabanov S
- Subjects
- High-Throughput Nucleotide Sequencing methods, Humans, Mutation, Reproducibility of Results, Leukemia, Myeloid, Acute diagnosis, Leukemia, Myeloid, Acute genetics, Myeloproliferative Disorders genetics
- Abstract
Next-generation sequencing has greatly advanced the molecular diagnostics of malignant hematological diseases and provides useful information for clinical decision making. Studies have shown that certain mutations are associated with prognosis and have a direct impact on treatment of affected patients. Therefore, reliable detection of pathogenic variants is critically important. Here, we compared four sequencing panels with different characteristics, from number of genes covered to technical aspects of library preparation and data analysis workflows, to find the panel with the best clinical utility for myeloid neoplasms with a special focus on acute myeloid leukemia. Using the Acrometrix Oncology Hotspot Control DNA and DNA from acute myeloid leukemia patients, panel performance was evaluated in terms of coverage, precision, recall, and reproducibility and different bioinformatics tools that can be used for the evaluation of any next-generation sequencing panel were tested. Taken together, our results support the reliability of the Acrometrix Oncology Hotspot Control to validate and compare sequencing panels for hematological diseases and show which panel-software combination (platform) has the best performance., (Copyright © 2022 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2022
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44. Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer.
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Taromi S, Firat E, Simonis A, Braun LM, Apostolova P, Elze M, Passlick B, Schumacher A, Lagies S, Frey A, Schmitt-Graeff A, Burger M, Schmittlutz K, Follo M, von Elverfeldt D, Zhu X, Kammerer B, Diederichs S, Duyster J, Manz MG, Niedermann G, and Zeiser R
- Subjects
- Animals, B7-H1 Antigen, Cell Line, Tumor, Humans, Immunotherapy, Adoptive, Mice, Neoplasm Recurrence, Local, Lung Neoplasms pathology, Small Cell Lung Carcinoma pathology, Small Cell Lung Carcinoma therapy
- Abstract
Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133
+ cancer stem cells and PD-L1+ CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease., (Copyright © 2022 Elsevier B.V. All rights reserved.)- Published
- 2022
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45. Retraction notice to "Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer" [Canc. Lett. 520 (2021) 385-399].
- Author
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Taromi S, Firat E, Simonis A, Braun LM, Apostolova P, Elze M, Passlick B, Schumacher A, Lagies S, Frey A, Schmitt-Graeff A, Burger M, Schmittlutz K, Follo M, von Elverfeldt D, Zhu X, Kammerer B, Diederichs S, Duyster J, Manz MG, Niedermann G, and Zeiser R
- Abstract
This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Following the publication of the above article, the Editor was notified that an error occurred in which all images were published with incorrect versions. The Editor has taken the decision that the manuscript is no longer acceptable in its current form, nor with a corrigendum, as the extensive changes to the figures and publication would lead to ambiguity for our readers. We have therefore made the decision to retract this manuscript from Cancer Letters with the possibility of resubmission and republication of the manuscript in its corrected form after peer review., (Copyright © 2022 Elsevier B.V. All rights reserved.)
- Published
- 2022
- Full Text
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46. Introducing innovative cellular therapies into the clinic: a 2-year retrospective experience of a chimeric antigen receptor T-cell programme at a single centre in Switzerland.
- Author
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Stolz S, Roncador M, Rösler W, Zenz T, Manz MG, Müller AMS, and Widmer CC
- Subjects
- Cytokine Release Syndrome, Humans, Lymphoma, B-Cell drug therapy, Neoplasm Recurrence, Local drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma drug therapy, Retrospective Studies, Switzerland, Immunotherapy, Adoptive adverse effects, Immunotherapy, Adoptive methods, Receptors, Chimeric Antigen therapeutic use
- Abstract
Aim of the Study: Chimeric antigen receptor T (CAR-T) cells are a powerful form of immune-cell therapy for patients with relapsed/refractory B-cell lymphoma and acute B lymphoblastic leukaemia. CAR-T cells have been commercially available in Switzerland since 2018. Because of the complexity and costs of this treatment it is critical to review patient outcomes in real-world settings, to examine whether the promising results from pivotal trials can be reproduced and to identify clinical parameters that determine their efficacy., Methods: Here we present results of a retrospective study analysing outcomes of patients treated with CAR-T cells in a single academic centre in Switzerland during the first two years after commercial approval (BASEC-No. 2020-02271). Cytokine release syndrome (CRS), immune-cell associated neurotoxicity syndrome (ICANS), responses to treatment, ancillary laboratory studies and administrative specifics of CAR-T treatment were examined and are discussed., Results: From October 2018 to August 2020 CAR-T cell therapy was evaluated in 34 patients, mostly with relapsed/refractory aggressive B-cell lymphoma (87% had refractory disease). Thirty-one patients underwent leukapheresis. Three of 31 patients (9.6%) died of rapid disease progression before the CAR-T cell product was delivered, two patients were enrolled into a clinical trial, three patients were not given CAR-T cells for other reasons. Ultimately, 23 patients were infused with a commercial CAR-T cell product and included in this analysis. Fourteen (61%) patients received bridging therapy while waiting for a median of 41 days (range 31-62) for delivery of the CAR-T cell product. Toxicity and severe side effects were rare (CRS >3 in 13%, ICANS > grade 3 in 10% of patients), manageable and resolved completely thereafter. The best overall response rate was 65%, with complete responses in 38% of lymphoma patients. At 12 months postinfusion, 61% of patients were alive and 35% progression free. With a median follow-up of 14 months, 13/23 (56%) patients were alive at the time of writing., Conclusion: CAR-T cell therapy proved to be safe and manageable under adequate hospital conditions. Outcomes resemble results from pivotal trials. The majority of patients was heavily pretreated and refractory at the time of CAR-T cell infusion. Patient selection, time point of leukapheresis, bridging strategies and timing of CAR-T cell infusion may be critical to further improve outcomes.
- Published
- 2022
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47. CAR T-cell Infusion Following Checkpoint Inhibition Can Induce Remission in Chemorefractory Post-transplant Lymphoproliferative Disorder of the CNS.
- Author
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Rösler W, Bink A, Bissig M, Imbach L, Marques Maggio E, Manz MG, Müller T, Roth P, Rushing E, Widmer C, Zenz T, von Moos S, and Müller AMS
- Published
- 2022
- Full Text
- View/download PDF
48. Antibodies from convalescent plasma promote SARS-CoV-2 clearance in individuals with and without endogenous antibody response.
- Author
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Marconato M, Abela IA, Hauser A, Schwarzmüller M, Katzensteiner R, Braun DL, Epp S, Audigé A, Weber J, Rusert P, Schindler E, Pasin C, West E, Böni J, Kufner V, Huber M, Zaheri M, Schmutz S, Frey BM, Kouyos RD, Günthard HF, Manz MG, and Trkola A
- Subjects
- Antibodies, Neutralizing, Antibodies, Viral, Antibody Formation, COVID-19 Vaccines, Humans, Immunization, Passive adverse effects, Proof of Concept Study, COVID-19 Serotherapy, COVID-19 therapy, SARS-CoV-2
- Abstract
BACKGROUNDNeutralizing antibodies are considered a key correlate of protection by current SARS-CoV-2 vaccines. The manner in which human infections respond to therapeutic SARS-CoV-2 antibodies, including convalescent plasma therapy, remains to be fully elucidated.METHODSWe conducted a proof-of-principle study of convalescent plasma therapy based on a phase I trial in 30 hospitalized COVID-19 patients with a median interval between onset of symptoms and first transfusion of 9 days (IQR, 7-11.8 days). Comprehensive longitudinal monitoring of the virological, serological, and disease status of recipients allowed deciphering of parameters on which plasma therapy efficacy depends.RESULTSIn this trial, convalescent plasma therapy was safe as evidenced by the absence of transfusion-related adverse events and low mortality (3.3%). Treatment with highly neutralizing plasma was significantly associated with faster virus clearance, as demonstrated by Kaplan-Meier analysis (P = 0.034) and confirmed in a parametric survival model including viral load and comorbidity (adjusted hazard ratio, 3.0; 95% CI, 1.1-8.1; P = 0.026). The onset of endogenous neutralization affected viral clearance, but even after adjustment for their pretransfusion endogenous neutralization status, recipients benefitted from plasma therapy with high neutralizing antibodies (hazard ratio, 3.5; 95% CI, 1.1-11; P = 0.034).CONCLUSIONOur data demonstrate a clear impact of exogenous antibody therapy on the rapid clearance of viremia before and after onset of the endogenous neutralizing response, and point beyond antibody-based interventions to critical laboratory parameters for improved evaluation of current and future SARS-CoV-2 therapies.TRIAL REGISTRATIONClinicalTrials.gov NCT04869072.FUNDINGThis study was funded via an Innovation Pool project by the University Hospital Zurich; the Swiss Red Cross Glückskette Corona Funding; Pandemiefonds of the UZH Foundation; and the Clinical Research Priority Program "Comprehensive Genomic Pathogen Detection" of the University of Zurich.
- Published
- 2022
- Full Text
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49. TP53 mutations confer resistance to hypomethylating agents and BCL-2 inhibition in myeloid neoplasms.
- Author
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Schimmer RR, Kovtonyuk LV, Klemm N, Fullin J, Stolz SM, Mueller J, Caiado F, Kurppa KJ, Ebert BL, Manz MG, and Boettcher S
- Subjects
- Humans, Mutation, Tumor Suppressor Protein p53 genetics, Neoplasms genetics, Proto-Oncogene Proteins c-bcl-2 genetics
- Published
- 2022
- Full Text
- View/download PDF
50. Proteomic identification of proliferation and progression markers in human polycythemia vera stem and progenitor cells.
- Author
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Tan G, Wolski WE, Kummer S, Hofstetter M, Theocharides APA, Manz MG, Aebersold R, and Meier-Abt F
- Subjects
- Cell Proliferation, Hematopoietic Stem Cells, Humans, Janus Kinase 2 genetics, NF-kappa B, Proteomics, Polycythemia Vera diagnosis, Polycythemia Vera genetics
- Abstract
Polycythemia vera (PV) is a stem cell disorder characterized by hyperproliferation of the myeloid lineages and the presence of an activating JAK2 mutation. To elucidate mechanisms controlling PV stem and progenitor cell biology, we applied a recently developed highly sensitive data-independent acquisition mass spectrometry workflow to purified hematopoietic stem and progenitor cell (HSPC) subpopulations of patients with chronic and progressed PV. We integrated proteomic data with genomic, transcriptomic, flow cytometry, and in vitro colony formation data. Comparative analyses revealed added information gained by proteomic compared with transcriptomic data in 30% of proteins with changed expression in PV patients. Upregulated biological pathways in hematopoietic stem and multipotent progenitor cells (HSC/MPPs) of PV included mammalian target of rapamycin (MTOR), STAT, and interferon signaling. We further identified a prominent reduction of clusterin (CLU) protein expression and a corresponding activation of nuclear factor-κB (NF-κB) signaling in HSC/MPPs of untreated PV patients compared with controls. Reversing the reduction of CLU and inhibiting NF-κB signaling decreased proliferation and differentiation of PV HSC/MPPs in vitro. Upon progression of PV, we identified upregulation of LGALS9 and SOCS2 protein expression in HSC/MPPs. Treatment of patients with hydroxyurea normalized the expression of CLU and NF-κB2 but not of LGALS9 and SOCS2. These findings expand the current understanding of the molecular pathophysiology underlying PV and provide new potential targets (CLU and NF-κB) for antiproliferative therapy in patients with PV., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
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