Publications by authors named "Markus G Manz"

176 Publications

Proteomic identification of proliferation and progression markers in human polycythemia vera stem and progenitor cells.

Blood Adv 2022 Jan 10. Epub 2022 Jan 10.

University of Zurich, Switzerland.

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 MTOR, STAT and interferon signaling. We further identified a prominent reduction of clusterin (CLU) protein expression and a corresponding activation of NFĸB signaling in HSC/MPPs of untreated PV patients compared with controls. Reversing the reduction of CLU and inhibiting NFĸB 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 NFĸB2, 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 NFĸB) for antiproliferative therapy in PV patients.
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http://dx.doi.org/10.1182/bloodadvances.2021005344DOI Listing
January 2022

The added value of multi-state modelling in a randomized controlled trial: The HOVON 102 study re-analyzed.

Cancer Med 2021 Dec 24. Epub 2021 Dec 24.

Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.

Clofarabine is an active antileukemic drug for subgroups of patients with acute myeloid leukemia (AML). Multi-state models can provide additional insights to supplement the original intention-to-treat analysis of randomized controlled trials (RCT). We re-analyzed the HOVON102/SAKK30/09 phase III RCT for newly diagnosed AML patients, which randomized between standard induction chemotherapy with or without clofarabine. Using multi-state models, we evaluated the effects of induction chemotherapy outcomes (complete remission [CR], measurable residual disease [MRD]), and post-remission therapy with allogeneic stem cell transplantation [alloSCT] on relapse and death. Through the latter a consistent reduction in the hazard of relapse in the clofarabine arm compared to the standard arm was found, which occurred irrespective of MRD status or post-remission treatment with alloSCT, demonstrating a strong and persistent antileukemic effect of clofarabine. During the time period between achieving CR and possible post-remission treatment with alloSCT, non-relapse mortality was higher in patients receiving clofarabine. An overall net benefit of treatment with clofarabine was identified using the composite endpoint current leukemia-free survival (CLFS). In conclusion, these results enforce and extend the earlier reported beneficial effect of clofarabine in AML and show that multi-state models further detail the effect of treatment on competing and series of events.
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http://dx.doi.org/10.1002/cam4.4392DOI Listing
December 2021

Multifactorial seroprofiling dissects the contribution of pre-existing human coronaviruses responses to SARS-CoV-2 immunity.

Nat Commun 2021 11 18;12(1):6703. Epub 2021 Nov 18.

Institute of Medical Virology, University of Zurich, Zurich, Switzerland.

Determination of SARS-CoV-2 antibody responses in the context of pre-existing immunity to circulating human coronavirus (HCoV) is critical for understanding protective immunity. Here we perform a multifactorial analysis of SARS-CoV-2 and HCoV antibody responses in pre-pandemic (N = 825) and SARS-CoV-2-infected donors (N = 389) using a custom-designed multiplex ABCORA assay. ABCORA seroprofiling, when combined with computational modeling, enables accurate definition of SARS-CoV-2 seroconversion and prediction of neutralization activity, and reveals intriguing interrelations with HCoV immunity. Specifically, higher HCoV antibody levels in SARS-CoV-2-negative donors suggest that pre-existing HCoV immunity may provide protection against SARS-CoV-2 acquisition. In those infected, higher HCoV activity is associated with elevated SARS-CoV-2 responses, indicating cross-stimulation. Most importantly, HCoV immunity may impact disease severity, as patients with high HCoV reactivity are less likely to require hospitalization. Collectively, our results suggest that HCoV immunity may promote rapid development of SARS-CoV-2-specific immunity, thereby underscoring the importance of exploring cross-protective responses for comprehensive coronavirus prevention.
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http://dx.doi.org/10.1038/s41467-021-27040-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8602384PMC
November 2021

Demethylating therapy increases anti-CD123 CAR T cell cytotoxicity against acute myeloid leukemia.

Nat Commun 2021 11 8;12(1):6436. Epub 2021 Nov 8.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.

Successful treatment of acute myeloid leukemia (AML) with chimeric antigen receptor (CAR) T cells is hampered by toxicity on normal hematopoietic progenitor cells and low CAR T cell persistence. Here, we develop third-generation anti-CD123 CAR T cells with a humanized CSL362-based ScFv and a CD28-OX40-CD3ζ intracellular signaling domain. This CAR demonstrates anti-AML activity without affecting the healthy hematopoietic system, or causing epithelial tissue damage in a xenograft model. CD123 expression on leukemia cells increases upon 5'-Azacitidine (AZA) treatment. AZA treatment of leukemia-bearing mice causes an increase in CTLA-4 anti-CD123 CAR T cell numbers following infusion. Functionally, the CTLA-4 anti-CD123 CAR T cells exhibit superior cytotoxicity against AML cells, accompanied by higher TNFα production and enhanced downstream phosphorylation of key T cell activation molecules. Our findings indicate that AZA increases the immunogenicity of AML cells, enhancing recognition and elimination of malignant cells by highly efficient CTLA-4 anti-CD123 CAR T cells.
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http://dx.doi.org/10.1038/s41467-021-26683-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8575966PMC
November 2021

Specific Inhibitor of Placental Alkaline Phosphatase Isolated from a DNA-Encoded Chemical Library Targets Tumor of the Female Reproductive Tract.

J Med Chem 2021 11 28;64(21):15799-15809. Epub 2021 Oct 28.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich), Vladimir-Prelog-Weg 4, 8093 Zürich, Switzerland.

Placental alkaline phosphatase (PLAP) is an abundant surface antigen in the malignancies of the female reproductive tract. Nevertheless, the discovery of PLAP-specific small organic ligands for targeting applications has been hindered by ligand cross-reactivity with the ubiquitous tissue non-specific alkaline phosphatase (TNAP). In this study, we used DNA-encoded chemical libraries to discover a potent (IC = 32 nM) and selective PLAP inhibitor, with no detectable inhibition of TNAP activity. Subsequently, the PLAP ligand was conjugated to fluorescein; it specifically bound to PLAP-positive tumors and targeted cervical cancer in a mouse model of the disease. Ultimately, the fluorescent derivative of the PLAP inhibitor functioned as a bispecific engager redirecting the killing of chimeric antigen receptor-T cells specific to fluorescein on PLAP-positive tumor cells.
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http://dx.doi.org/10.1021/acs.jmedchem.1c01103DOI Listing
November 2021

Chronic viral infections persistently alter marrow stroma and impair hematopoietic stem cell fitness.

J Exp Med 2021 12 28;218(12). Epub 2021 Oct 28.

Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland.

Chronic viral infections are associated with hematopoietic suppression, bone marrow (BM) failure, and hematopoietic stem cell (HSC) exhaustion. However, how persistent viral challenge and inflammatory responses target BM tissues and perturb hematopoietic competence remains poorly understood. Here, we combine functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus leads to (1) long-lasting decimation of the BM stromal network of mesenchymal CXCL12-abundant reticular cells, (2) proinflammatory transcriptional remodeling of remaining components of this key niche subset, and (3) durable functional defects and decreased competitive fitness in HSCs. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined antibody-mediated inhibition of type I and II IFN pathways completely preempts degeneration of CARc and protects HSCs from chronic dysfunction. Hence, viral infections and ensuing immune reactions durably impact BM homeostasis by persistently decreasing the competitive fitness of HSCs and disrupting essential stromal-derived, hematopoietic-supporting cues.
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http://dx.doi.org/10.1084/jem.20192070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8558839PMC
December 2021

Baseline creatinine predicts acute kidney injury during intensive therapy in transplant-eligible patients with acute myeloid leukaemia.

Br J Haematol 2021 Oct 5. Epub 2021 Oct 5.

Department of Medical Oncology and Haematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1111/bjh.17854DOI Listing
October 2021

CXCL12-abundant reticular cells are the major source of IL-6 upon LPS stimulation and thereby regulate hematopoiesis.

Blood Adv 2021 12;5(23):5002-5015

Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.

Hematopoiesis is maintained by hematopoietic stem and progenitor cells that are located in the bone marrow (BM) where they are embedded within a complex supportive microenvironment consisting of a multitude of various non-hematopoietic and hematopoietic cell types. The BM microenvironment not only regulates steady-state hematopoiesis by provision of growth factors, cytokines, and cell-cell contact but is also an emerging key player during the adaptation to infectious and inflammatory insults (emergency hematopoiesis). Through a combination of gene expression analyses in prospectively isolated non-hematopoietic BM cell populations and various mouse models, we found that BM CXCL12-abundant reticular (CAR) cells are a major source of systemic and local BM interleukin-6 (IL-6) levels during emergency hematopoiesis after lipopolysaccharide (LPS) stimulation. Importantly, although IL-6 is dispensable during the initial phase of LPS-induced emergency hematopoiesis, it is required to sustain an adequate hematopoietic output during chronic repetitive inflammation. Our data highlight the essential role of the non-hematopoietic BM microenvironment for the sensing and integration of pathogen-derived signals into sustained demand-adapted hematopoietic responses.
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http://dx.doi.org/10.1182/bloodadvances.2021005531DOI Listing
December 2021

IL-1 mediates microbiome-induced inflammaging of hematopoietic stem cells in mice.

Blood 2022 Jan;139(1):44-58

Department of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center Zurich, University of Zurich, Zurich, Switzerland.

Aging is associated with impaired hematopoietic and immune function caused in part by decreased fitness in the hematopoietic stem cell (HSC) population and an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. Here we demonstrate that older specific pathogen free (SPF) wild-type (WT) mice in contrast to young SPF mice produce more interleukin-1a and interleukin-1b (IL-1a/b) in steady-state bone marrow (BM), with most of the IL-1a/b being derived from myeloid BM cells. Furthermore, blood from steady-state older SPF WT mice contains higher levels of microbe-associated molecular patterns, specifically TLR4 and TLR8 ligands. In addition, BM myeloid cells from older mice produce more IL-1b in vitro, and older mice show higher and more durable IL-1a/b responses upon stimulation with lipopolysaccharide in vivo. To test whether HSC aging is driven by IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knockout (KO) mice. Indeed, older HSCs from IL-1R1KO mice show significantly mitigated aging-associated inflammatory signatures. Moreover, HSCs from older IL-1R1KO and from germ-free mice maintain unbiased lymphomyeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in older WT mice was similarly sufficient to reverse myeloid-biased output of their HSC populations. Collectively, our data define the microbiome/IL-1/IL-1R1 axis as a key, self-sustaining and also therapeutically partially reversible driver of HSC inflammaging.
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http://dx.doi.org/10.1182/blood.2021011570DOI Listing
January 2022

Commensal Clostridiales strains mediate effective anti-cancer immune response against solid tumors.

Cell Host Microbe 2021 10 27;29(10):1573-1588.e7. Epub 2021 Aug 27.

Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Despite overall success, T cell checkpoint inhibitors for cancer treatment are still only efficient in a minority of patients. Recently, intestinal microbiota was found to critically modulate anti-cancer immunity and therapy response. Here, we identify Clostridiales members of the gut microbiota associated with a lower tumor burden in mouse models of colorectal cancer (CRC). Interestingly, these commensal species are also significantly reduced in CRC patients compared with healthy controls. Oral application of a mix of four Clostridiales strains (CC4) in mice prevented and even successfully treated CRC as stand-alone therapy. This effect depended on intratumoral infiltration and activation of CD8 T cells. Single application of Roseburia intestinalis or Anaerostipes caccae was even more effective than CC4. In a direct comparison, the CC4 mix supplementation outperformed anti-PD-1 therapy in mouse models of CRC and melanoma. Our findings provide a strong preclinical foundation for exploring gut bacteria as novel stand-alone therapy against solid tumors.
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http://dx.doi.org/10.1016/j.chom.2021.08.001DOI Listing
October 2021

Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer.

Cancer Lett 2021 11 15;520:385-399. Epub 2021 Aug 15.

Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; BIOSS Center for Biological Signalling Studies, University of Freiburg, Germany; Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Germany.

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-L1CD73 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.
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http://dx.doi.org/10.1016/j.canlet.2021.08.012DOI Listing
November 2021

Asymmetric organelle inheritance predicts human blood stem cell fate.

Blood 2021 Jul 27. Epub 2021 Jul 27.

ETH Zurich, Basel, Switzerland.

Understanding human hematopoietic stem cell fate control is important for their improved therapeutic manipulation. Asymmetric cell division, the asymmetric inheritance of factors during division instructing future daughter cell fates, was recently described in mouse blood stem cells. In human blood stem cells, the possible existence of asymmetric cell division remained unclear due to technical challenges in its direct observation. Here, we use long-term quantitative single-cell imaging to show that lysosomes and active mitochondria are asymmetrically inherited in human blood stem cells and that their inheritance is a coordinated, non-random process. Furthermore, multiple additional organelles, including autophagosomes, mitophagosomes, autolysosomes and recycling endosomes show preferential asymmetric co-segregation with lysosomes. Importantly, asymmetric lysosomal inheritance predicts future asymmetric daughter cell cycle length, differentiation and stem cell marker expression, while asymmetric inheritance of active mitochondria correlates with daughter metabolic activity. Hence, human hematopoietic stem cell fates are regulated by asymmetric cell division, with both mechanistic evolutionary conservation and differences to the mouse system.
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http://dx.doi.org/10.1182/blood.2020009778DOI Listing
July 2021

Daratumumab in rituximab-refractory autoimmune haemolytic anaemia.

Br J Haematol 2021 09 28;194(5):931-934. Epub 2021 Jun 28.

Department of Medical Oncology and Hematology, University Hospital of Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1111/bjh.17655DOI Listing
September 2021

Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection.

J Exp Med 2021 07 15;218(7). Epub 2021 Jun 15.

Department of Medical Oncology and Hematology, University Hospital Zürich, Zürich, Switzerland.

Inflammation is an evolutionarily selected defense response to infection or tissue damage that involves activation and consumption of immune cells in order to reestablish and maintain organismal integrity. In this process, hematopoietic stem cells (HSCs) are themselves exposed to inflammatory cues and via proliferation and differentiation, replace mature immune cells in a demand-adapted fashion. Here, we review how major sources of systemic inflammation act on and subsequently shape HSC fate and function. We highlight how lifelong inflammatory exposure contributes to HSC inflamm-aging and selection of premalignant HSC clones. Finally, we explore emerging areas of interest and open questions remaining in the field.
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http://dx.doi.org/10.1084/jem.20201541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8210622PMC
July 2021

Bimodal expression of potential drug target CLL-1 (CLEC12A) on CD34+ blasts of AML patients.

Eur J Haematol 2021 Sep 26;107(3):343-353. Epub 2021 Jun 26.

Department of Development of Science, Genentech, South San Francisco, CA, USA.

Objectives: This study aims to retrospectively assess C-lectin-like molecule 1 (CLL-1) bimodal expression on CD34+ blasts in acute myeloid leukemia (AML) patients (total N = 306) and explore potential CLL-1 bimodal associations with leukemia and patient-specific characteristics.

Methods: Flow cytometry assays were performed to assess the deeper immunophenotyping of CLL-1 bimodality. Cytogenetic analysis was performed to characterize the gene mutation on CLL-1-negative subpopulation of CLL-1 bimodal AML samples.

Results: The frequency of a bimodal pattern of CLL-1 expression of CD34 blasts ranged from 8% to 65% in the different cohorts. Bimodal CLL-1 expression was most prevalent in patients with MDS-related AML (P = .011), ELN adverse risk (P = .002), NPM1 wild type (WT, P = .049), FLT3 WT (P = .035), and relatively low percentages of leukemia-associated immunophenotypes (P = .006). Additional immunophenotyping analysis revealed the CLL-1 subpopulation may consist of pre-B cells, immature myeloblasts, and hematopoietic stem cells. Furthermore, (pre)-leukemic mutations were detected in both CLL-1 and CLL-1 subfractions of bimodal samples (N = 3).

Conclusions: C-lectin-like molecule 1 bimodality occurs in about 25% of AML patients and the CLL-1 cell population still contains malignant cells, hence it may potentially limit the effectiveness of CLL-1-targeted therapies and warrant further investigation.
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http://dx.doi.org/10.1111/ejh.13672DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8457079PMC
September 2021

Cytokine combinations for human blood stem cell expansion induce cell-type- and cytokine-specific signaling dynamics.

Blood 2021 09;138(10):847-857

Department of Biosystems Science and Engineering, Eidgenössische Technische Hochschule (ETH) Zurich, Basel, Switzerland.

How hematopoietic stem cells (HSCs) integrate signals from their environment to make fate decisions remains incompletely understood. Current knowledge is based on either averages of heterogeneous populations or snapshot analyses, both missing important information about the dynamics of intracellular signaling activity. By combining fluorescent biosensors with time-lapse imaging and microfluidics, we measured the activity of the extracellular-signal-regulated kinase (ERK) pathway over time (ie, dynamics) in live single human umbilical cord blood HSCs and multipotent progenitor cells (MPPs). In single cells, ERK signaling dynamics were highly heterogeneous and depended on the cytokines, their combinations, and cell types. ERK signaling was activated by stem cell factor (SCF) and FMS-like tyrosine kinase 3 ligand in HSCs but SCF, interleukin 3, and granulocyte colony-stimulating factor in MPPs. Different cytokines and their combinations led to distinct ERK signaling dynamics frequencies, and ERK dynamics in HSCs were more transient than those in MPPs. A combination of 5 cytokines recently shown to maintain HSCs in long-term culture, had a more-than-additive effect in eliciting sustained ERK dynamics in HSCs. ERK signaling dynamics also predicted future cell fates. For example, CD45RA expression increased more in HSC daughters with intermediate than with transient or sustained ERK signaling. We demonstrate heterogeneous cytokine- and cell-type-specific ERK signaling dynamics, illustrating their relevance in regulating hematopoietic stem and progenitor (HSPC) cell fates.
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http://dx.doi.org/10.1182/blood.2020008386DOI Listing
September 2021

BRAF-induced senescence drives Langerhans cell histiocytosis pathophysiology.

Nat Med 2021 05 6;27(5):851-861. Epub 2021 May 6.

Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Langerhans cell histiocytosis (LCH) is a potentially fatal condition characterized by granulomatous lesions with characteristic clonal mononuclear phagocytes (MNPs) harboring activating somatic mutations in mitogen-activated protein kinase (MAPK) pathway genes, most notably BRAF. We recently discovered that the BRAF mutation can also affect multipotent hematopoietic progenitor cells (HPCs) in multisystem LCH disease. How the BRAF mutation in HPCs leads to LCH is not known. Here we show that enforced expression of the BRAF mutation in early mouse and human multipotent HPCs induced a senescence program that led to HPC growth arrest, apoptosis resistance and a senescence-associated secretory phenotype (SASP). SASP, in turn, promoted HPC skewing toward the MNP lineage, leading to the accumulation of senescent MNPs in tissue and the formation of LCH lesions. Accordingly, elimination of senescent cells using INK-ATTAC transgenic mice, as well as pharmacologic blockade of SASP, improved LCH disease in mice. These results identify senescent cells as a new target for the treatment of LCH.
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http://dx.doi.org/10.1038/s41591-021-01304-xDOI Listing
May 2021

Neurological complications of cancer immunotherapy.

Cancer Treat Rev 2021 Jun 23;97:102189. Epub 2021 Mar 23.

Division of Oncology, Department of Medicine I, Medical University of Vienna, Austria.

Immunotherapy has emerged as a powerful therapeutic approach in many areas of clinical oncology and hematology. The approval of ipilimumab, a monoclonal antibody targeting the immune cell receptor CTLA-4, has marked the beginning of the era of immune checkpoint inhibitors. In the meantime, numerous antibodies targeting the PD-1 pathway have expanded the class of clinically approved immune checkpoint inhibitors. Furthermore, novel antibodies directed against other immune checkpoints are currently in clinical evaluation. More recently, bispecific antibodies, which link T cells directly to tumor cells as well as adoptive T cell transfer with immune cells engineered to express a chimeric antigen receptor, have been approved in certain indications. Neurological complications associated with the use of these novel immunotherapeutic concepts have been recognized more and more frequently. Immune checkpoint inhibitors may cause various neurological deficits mainly by alterations of the peripheral nervous system's integrity. These include radiculopathies, neuropathies, myopathies as well as myasthenic syndromes. Side effects involving the central nervous system are less frequent but may result in severe clinical symptoms and syndromes. The administration of chimeric antigen receptor (CAR) T cell is subject to rigorous patient selection and their use is frequently associated with neurological complications including encephalopathy and seizures, which require immediate action and appropriate therapeutic measures. Close clinical monitoring for neurological symptoms is key for early recognition of immunotherapy-related side effects. Comprehensive diagnostic work-up and adequate therapeutic measures are essential to avoid further clinical deterioration and residual neurological deficits.
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http://dx.doi.org/10.1016/j.ctrv.2021.102189DOI Listing
June 2021

Stereo- and regiodefined DNA-encoded chemical libraries enable efficient tumour-targeting applications.

Nat Chem 2021 06 8;13(6):540-548. Epub 2021 Apr 8.

Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zurich), Zurich, Switzerland.

The encoding of chemical compounds with amplifiable DNA tags facilitates the discovery of small-molecule ligands for proteins. To investigate the impact of stereo- and regiochemistry on ligand discovery, we synthesized a DNA-encoded library of 670,752 derivatives based on 2-azido-3-iodophenylpropionic acids. The library was selected against multiple proteins and yielded specific ligands. The selection fingerprints obtained for a set of protein targets of pharmaceutical relevance clearly showed the preferential enrichment of ortho-, meta- or para-regioisomers, which was experimentally verified by affinity measurements in the absence of DNA. The discovered ligands included novel selective enzyme inhibitors and binders to tumour-associated antigens, which enabled conditional chimeric antigen receptor T-cell activation and tumour targeting.
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http://dx.doi.org/10.1038/s41557-021-00660-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8405038PMC
June 2021

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort.

Ann Hematol 2021 May 2;100(5):1169-1179. Epub 2021 Mar 2.

Institute of Medical Genetics and Pathology, University Hospital Basel, Schoenbeinstrasse 40, 4031, Basel, Switzerland.

This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response.
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http://dx.doi.org/10.1007/s00277-021-04467-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043896PMC
May 2021

Addition of lenalidomide to intensive treatment in younger and middle-aged adults with newly diagnosed AML: the HOVON-SAKK-132 trial.

Blood Adv 2021 02;5(4):1110-1121

Medisch Spectrum Leeuwarden, Leeuwarden, The Netherlands.

Lenalidomide, an antineoplastic and immunomodulatory drug, has therapeutic activity in acute myeloid leukemia (AML), but definitive studies about its therapeutic utility have been lacking. In a phase 3 study, we compared 2 induction regimens in newly diagnosed patients age 18 to 65 years with AML: idarubicine-cytarabine (cycle 1) and daunorubicin and intermediate-dose cytarabine (cycle 2) without or with lenalidomide (15 mg orally on days 1-21). One final consolidation cycle of chemotherapy or autologous stem cell transplantation (auto-SCT) or allogeneic SCT (allo-SCT) was provided according to a prognostic risk and minimal residual disease (MRD)-adapted approach. Event-free survival (EFS; primary end point) and other clinical end points were assessed. A second random assignment in patients in complete response or in complete response with incomplete hematologic recovery after cycle 3 or auto-SCT involved 6 cycles of maintenance with lenalidomide (10 mg on days 1-21) or observation. In all, 392 patients were randomly assigned to the control group, and 388 patients were randomly assigned to lenalidomide induction. At a median follow-up of 41 months, the study revealed no differences in outcome between the treatments (EFS, 44% ± 2% standard error and overall survival, 54% ± 2% at 4 years for both arms) although in an exploratory post hoc analysis, a lenalidomide benefit was suggested in SRSF2-mutant AML. In relation to the previous Dutch-Belgian Hemato-Oncology Cooperative Group and Swiss Group for Clinical Cancer Research (HOVON-SAKK) studies that used a similar 3-cycle regimen but did not pursue an MRD-guided approach, these survival estimates compare markedly more favorably. MRD status after cycle 2 lost prognostic value in intermediate-risk AML in the risk-adjusted treatment context. Maintenance with lenalidomide showed no apparent effect on relapse probability in 88 patients randomly assigned for this part of the study.
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http://dx.doi.org/10.1182/bloodadvances.2020003855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903238PMC
February 2021

Anti-CD117 immunotherapy to eliminate hematopoietic and leukemia stem cells.

Exp Hematol 2021 03 20;95:31-45. Epub 2021 Jan 20.

Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Comprehensive Cancer Center Zurich (CCCZ), Zurich, Switzerland. Electronic address:

Precise replacement of diseased or dysfunctional organs is the goal of regenerative medicine and has appeared to be a distant goal for a long time. In the field of hematopoietic stem cell transplantation, this goal is now becoming tangible as gene-editing technologies and novel conditioning agents are entering the clinical arena. Targeted immunologic depletion of hematopoietic stem cells (HSCs), which are at the very root of the hematopoietic system, will enable more selective and potentially more effective hematopoietic stem cell transplantation in patients with hematological diseases. In contrast to current conditioning regimes based on ionizing radiation and chemotherapy, immunologic conditioning will spare mature hematopoietic cells and cause substantially less inflammation and unspecific collateral damage to other organs. Biological agents that target the stem cell antigen CD117 are the frontrunners for this purpose and have exhibited preclinical activity in depletion of healthy HSCs. The value of anti-CD117 antibodies as conditioning agents is currently being evaluated in early clinical trials. Whereas mild, antibody-based immunologic conditioning concepts might be appropriate for benign hematological disorders in which incomplete replacement of diseased cells is sufficient, higher efficacy will be required for treatment and elimination of hematologic stem cell malignancies such as acute myeloid leukemia and myelodysplastic syndrome. Antibody-drug conjugates, bispecific T-cell engaging and activating antibodies (TEAs), or chimeric antigen receptor (CAR) T cells might offer increased efficacy compared with naked antibodies and yet higher tolerability and safety compared with current genotoxic conditioning approaches. Here, we summarize the current state regarding immunologic conditioning concepts for the treatment of HSC disorders and outline potential future developments.
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http://dx.doi.org/10.1016/j.exphem.2021.01.003DOI Listing
March 2021

The Tumor Profiler Study: integrated, multi-omic, functional tumor profiling for clinical decision support.

Cancer Cell 2021 03 21;39(3):288-293. Epub 2021 Jan 21.

Roche Pharmaceutical Research and Early Development, Roche Innovation Center Zurich, Wagistrasse 10, 8952 Schlieren, Switzerland.

The application and integration of molecular profiling technologies create novel opportunities for personalized medicine. Here, we introduce the Tumor Profiler Study, an observational trial combining a prospective diagnostic approach to assess the relevance of in-depth tumor profiling to support clinical decision-making with an exploratory approach to improve the biological understanding of the disease.
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http://dx.doi.org/10.1016/j.ccell.2021.01.004DOI Listing
March 2021

Clonal hematopoiesis in hematopoietic stem cell transplantation.

Curr Opin Hematol 2021 03;28(2):94-100

Department of Medical Oncology and Hematology, University Hospital Zurich and University of Zurich, Zurich, Switzerland.

Purpose Of Review: Clonal hematopoiesis (CH) is characterized by the acquisition of somatic mutations and subsequent expansion of mutated hematopoietic stem and progenitor cell (HSPC) clones without clinical evidence for a hematologic neoplasm. The prevalence of CH continuously increases with age reaching double-digit percentages in individuals >60 years. CH is associated with an increased risk for hematologic neoplasms and cardiovascular disease. We will review recent efforts to investigate how CH influences patient outcomes in hematopoietic stem cell transplantation - both autologous (ASCT) and allogeneic (allo-HSCT).

Recent Findings: Donor-engrafted CH is common in allo-HSCT recipients. Apart from a higher incidence of chronic GvHD and the rare but devastating complication of donor-derived leukemia, CH does not appear to negatively impact outcomes in allo-HSCT recipients. In lymphoma patients undergoing ASCT, however, CH is associated with an excess mortality driven by therapy-related myeloid neoplasms and cardiovascular events. Interestingly, inferior overall survival in patients with CH undergoing ASCT for multiple myeloma (MM) is due to an increased rate of MM progression.

Summary: CH is highly prevalent in both allo-HSCT and ASCT patients suggesting a clinically relevant but context-dependent impact on adverse outcomes. Given the current lack of therapeutic interventions, systematic screening for CH in the transplant setting is currently not indicated outside of clinical studies.
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http://dx.doi.org/10.1097/MOH.0000000000000631DOI Listing
March 2021
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