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Publications (494)
Objectives
To explore efficacy and safety of CD19-directed Chimeric Antigen Receptor (CAR) T cell therapy in a patient with Jo1-Antisynthetase-syndrome (ASyS) refractory to multiple immunosuppressants, including anti-CD38 therapy, and review published cases on CAR T cell therapy in idiopathic inflammatory myopathies (IIM).
Methods
Following lympho...
CD8+ T cells are a vital branch of the adaptive immune response. They are necessary for an effective antiviral and anticancer immunity, which is mediated through their cytotoxic effector functions. CD8+ T cell activation, proliferation, and effector functions are dependent on a complex network of Ca2+ signalling pathways involving both Ca2+ release...
Background:
Allogeneic hematopoietic stem-cell transplantation is the only curative treatment for myelofibrosis. Driver mutations are the pathophysiological hallmark of the disease, but the role of mutation clearance after transplantation is unclear.
Methods:
We used highly sensitive polymerase-chain-reaction technology to analyze the dynamics o...
Toleration of a semi-allogeneic fetus in the mother’s uterus as well as tolerance after allogeneic hematopoietic stem cell transplantation (HSCT) appear to share some immunologic concepts. The existence of microchimeric cells, and the original idea of a bidirectional cell trafficking between mother and child during pregnancy have been known for dec...
Despite the introduction of JAK inhibitors, allogeneic hematopoietic cell transplant remains the only potentially curative treatment for patients with myelofibrosis but has considerable treatment‐related complications. Whether the incorporation of JAK inhibition into the transplant algorithm leads to improved outcomes is still unclear. Here, we ana...
Background Driver mutations (JAK2, CALR, and MPL) are the pathophysiologic hallmark of myelofibrosis. Around 90% of myelofibrosis patients harbor one of the three mutations, which can be measured in peripheral blood. Driver mutation clearance on day 30 after allogeneic hematopoietic cell transplantation (HCT) is a strong predictor of disease progre...
In multiple sclerosis (MS) disease progression is driven by chronic low-grade neuroinflammation leading to neuronal dysregulation. B cell directed monoclonal antibodies are effective, yet fail to halt disease progression, likely because of their inability to access, compartmentalization of neuroinflammation in the central nervous system (CNS). In t...
Recent years have witnessed the success of αβ T cells engineered to express chimeric antigen receptors (CARs) in treating haematological cancers. CARs combine the tumour antigen binding capability of antibodies with the signalling functions of the T‐cell receptor (TCR) ζ chain and co‐stimulatory receptors. Despite the success, αβ CAR T cells face l...
Background: Remarkable differences exist in the outcome of systemic cancer therapies. Lymphomas and leukemias generally respond well to systemic chemotherapies, while solid cancers often fail. We engineered different human cancer cells lines to uniformly express a modified herpes simplex virus thymidine kinase TK.007 as a suicide gene when ganciclo...
Pro-inflammatory CD4 ⁺ T cells are major drivers of autoimmune diseases, yet therapies modulating T cell phenotypes to promote an anti-inflammatory state are lacking. Here, we identify T helper 17 (T H 17) cell plasticity in the kidneys of patients with antineutrophil cytoplasmic antibody–associated glomerulonephritis on the basis of single-cell (s...
The invention relates to an antibody for use in a therapy involving the cytotoxic elimination of a target cell by engaging the target cell with an immune effector cell, the antibody comprising a first binding domain binding to an epitope on a surface protein present on the surface of the target cell and a second binding domain binding to an epitope...
Due to their exceptional solubility and stability, nanobodies have emerged as powerful building blocks for research tools and therapeutics. However, their generation in llamas is cumbersome and costly. Here, by inserting an engineered llama immunoglobulin heavy chain (IgH) locus into IgH-deficient mice, we generate a transgenic mouse line, which we...
Duchenne muscular dystrophy (DMD) is a severe monogenic hereditary disease with early manifestation and a progressive course. Treatment options have so far been limited. Gene therapy opens up new options for DMD patients.
Against the background of a further death following DMD gene therapy, the side effects and risks of the gene therapeutics alread...
The TAM (TYRO3, AXL, and MERTK) family of receptor tyrosine kinases exhibit cell-transforming capacity promoting tumorigenesis, metastasis and therapy-resistance in various cancer entities. GAS6-MERTK axis represents a target in Multiple Myeloma (MM) to inhibit tumor progression. We sought to explore the role of the alternative TAM receptor ligand...
The cellular basis of cancer immune surveillance, already hypothesized in ancient times, was only proven with the advent of HCT. Indeed, the discovery of the nature of GVHD and its antileukemic effects (Weiden et al. 1979) was followed by the first successful attempts of adoptive immunotherapy using donor leukocytes (Kolb et al. 1990). To address t...
With permanently increasing prevalence, allergies have become a worldwide healthcare problem. Symptoms are very diverse and can range from relatively mild ones, e.g. itching and sneezing, via severe breathing difficulties and chronically impaired quality of life up to life‐threatening allergic shock. In type I‐allergic diseases such as allergic ast...
TO THE EDITOR: Minimal residual disease (MRD) is a well-established prognostic marker that allows subdivision of AML patients into different risk groups independently of the methods being used and cutoffs [1-3]. Moreover, the MRD status may be used to guide the use of intensive (e.g. allo-SCT) or non-intensive (e.g. chemotherapy and/ or autologous...
Simple Summary
Chimeric antigen receptors (CARs) are used to recognize highly specific antigens (“mugshots”) to target immune effectors (“policemen”) against cancer cells. Whereas this new immunotherapy has already set novel standards in the treatment of some specific types of blood cancer, it has not yet been successful with most blood (and solid)...
Zusammenfassung
Der umfassende Aufschwung der klinischen Gentherapie seit ca. 2010 (vgl. „Fünfter Gentechnologiebericht“ ) hat sich in den vergangenen Jahren fortgesetzt und konsolidiert. Der daraus resultierende breite Einstieg großer Biotech- und Pharmafirmen führte zu einer deutlich verbesserten materiellen und technologischen Basis, sowohl im B...
Zusammenfassung
Die genetische Information, die als Bauplan für das menschliche Leben dient, ist in der chromosomalen DNA eines jeden Zellkerns und in der DNA unserer zellulären Kraftwerke, den Mitochondrien, gespeichert. Im menschlichen Körper ist die Expression der Gene gut reguliert und ihr orchestriertes Zusammenspiel erlaubt die Spezialisierun...
Zusammenfassung
Der vorliegende Band zur Gen- und Zelltherapie schließt an eine Reihe einschlägiger Kapitel in den bisher vorgelegten Gentechnologieberichten 1–5 sowie spezifischer Themenbände der AG Gentechnologiebericht an. Wie bisher wurden die unterschiedlichen Kapitel von in dem jeweiligen Fachgebiet bestens ausgewiesenen Expertinnen und Exper...
Zusammenfassung
Die Idee, vererbbare Krankheiten durch eine Korrektur der ihnen zugrunde liegenden genetischen Defekte zu behandeln oder ihren Ausbruch im Idealfall sogar zu verhindern, wurde seit Beginn der 1960er-Jahre diskutiert, u. a. in Arbeiten der beiden Nobelpreisträger Joshua Lederberg (Lederberg 1966) und Edward Tatum (Tatum 1966). Beide...
Zusammenfassung
Die Transplantation von Zellen und Organen war über Jahrhunderte ein Ziel der Medizin. Die hämatopoetische Stammzelltransplantation, d. h. die Übertragung des blutbildenden Systems von einem Spender auf einen Empfänger, ist die am längsten etablierte und seit Jahrzehnten erfolgreiche Anwendung in der Transplantationsmedizin.
Hepatocellular carcinoma (HCC) results in high mortality due to ineffective systemic therapy. Human immortalized cell lines are commonly used to study anti-tumor effects in the context of new anti-tumor therapies and tumor biology. As immortalized cell lines have limited biological relevance and heterogeneity compared to primary cells, patient-deri...
Background & Aims: The liver is one of the organs most commonly affected by metastasis. The presence of liver metastases has been reported to be responsible for an immunosuppressive microenvironment and diminished immunotherapy efficacy. Herein, we aimed to investigate the role of IL-10 in liver metastasis and to determine how its modulation could...
Hepatocellular carcinoma (HCC) results in high mortality due to ineffective systemic therapy. Human immortalized cell lines are commonly used to study anti-tumour effects in the context of new anti-tumour therapies and tumour biology. As immortalized cell lines have limited biological relevance and heterogeneity compared to primary cells, patient-d...
Background
The discovery of prognostically informative mutations in patients with primary myelofibrosis (PMF) prompted the development of mutation-enhanced risk scores. Among these mutations, those in ASXL1 are invariably associated with adverse outcome, either as single variants or as part of a high-mutation-risk category (HMR) including SRSF2, EZ...
Myelofibrosis is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) characterized by clonal myeloproliferation. Allogeneic hematopoietic stem-cell transplantation is the only potentially curative treatment for patients with myelofibrosis. With that, it can resolve fibrosis and lead to complete loss of the clonal burden....
Objective
Primary sclerosing cholangitis (PSC) is characterised by bile duct strictures and progressive liver disease, eventually requiring liver transplantation. Although the pathogenesis of PSC remains incompletely understood, strong associations with HLA-class II haplotypes have been described. As specific HLA-DP molecules can bind the activatin...
The complex morphology of neurons poses a challenge for proteostasis because the majority of lysosomal degradation machinery is present in the cell soma. In recent years, however, mature lysosomes were identified in dendrites, and a fraction of those appear to fuse with the plasma membrane and release their content to the extracellular space. Here,...
The CRISPR/Cas system has a broad range of possible medical applications, but its clinical translation has been hampered, particularly by the lack of safe and efficient vector systems mediating the short-term expression of its components. Recently, different virus-like particles (VLPs) have been introduced as promising vectors for the delivery of C...
Hematopoietic cell transplantation (HCT) is a curative approach for myelofibrosis patients, but relapse is a major cause of treatment failure. We investigated the effect of donor lymphocyte infusion (DLI) in 37 patients with molecular (n = 17) or hematological relapse (n = 20) after HCT. Patients received median of 2 (range, 1–5) cumulative DLI (to...
Microglia arise from the yolk sac and enter the brain during early embryogenesis. Upon entry, microglia undergo in situ proliferation and eventually colonize the entire brain by the third postnatal week in mice. However, the intricacies of their developmental expansion remain unclear. Here, we characterize the proliferative dynamics of microglia du...
Immune therapies have revolutionized the treatment of cancer, however, until now only a minority of patients derive long-term benefit. Notably, despite widely reported significant differences between the immune system of males and females, there continues to exist a knowledge gap regarding sex disparities in anti-cancer immune responses. Recent met...
Splenomegaly is a hallmark of myelofibrosis (MF), and reports on the impact of spleen size on the outcome of allo-HSCT have been conflicting, possibly due to differences in methods of assessment. We retrospectively analysed the impact of spleen volume and length measured by computed tomography on allo-HSCT outcome in 93 patients, 74% of whom had pr...
CD19-specific chimeric antigen receptor (CD19-CAR)-T cell therapies mediate durable responses in late-stage B-cell malignancies, but can be complicated by a potentially severe immune effector cell-associated neurotoxicity syndrome (ICANS). Despite broad efforts, the precise mechanisms of ICANS are not entirely known, and resistance to current ICANS...
Microglia are the resident immune cells of the brain and arise from yolk sac-derived macrophages during early embryogenesis. On entering the brain, microglia undergo in situ proliferation and eventually colonise the entire brain by the second and third postnatal weeks in mice. However, the intricate dynamics of their developmental expansion remain...
Microglia are the resident immune cells of the brain and arise from yolk sac-derived macrophages during early embryogenesis. On entering the brain, microglia undergo in situ proliferation and eventually colonise the entire brain by the second and third postnatal weeks in mice. However, the intricate dynamics of their developmental expansion remain...
For patients with myelofibrosis, allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment to date. Busulfan-based conditioning regimens are commonly used, although high inter-individual variability (IIV) in busulfan drug exposure makes individual dose selection challenging. Since data regarding the IIV in p...
The Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV-2) has continuously evolved, resulting in the emergence of several variants of concern (VOCs). To study mechanisms of viral entry and potentially identify specific inhibitors, we pseudotyped lentiviral vectors with different SARS-CoV-2 VOC spike variants (D614G, Alpha, Beta, Delta,...
COVID‐19, caused by SARS‐CoV‐2, has emerged as a global pandemic. While immune responses of the adaptive immune system have been in the focus of research, the role of NK cells in COVID‐19 remains less well understood. Here we characterized NK cell‐mediated SARS‐CoV‐2 antibody‐dependent cellular cytotoxicity (ADCC) against SARS‐CoV‐2 spike‐1 (S1) an...
The epithelial cell adhesion molecule (EpCAM) and Thy-1 cell surface antigen (CD90) have been implicated as cancer stem cell (CSC) markers in hepatocellular carcinoma (HCC). Expression of EpCAM and CD90 on HCC cells is associated with increased tumorigenicity, metastasis and poor prognosis. In this study, we demonstrate that combined treatment with...
Hematopoietic stem cell transplantation (HSCT) represents the only curative treatment option for numerous hematologic malignancies. While the influence of donor age and the composition of the graft have already been examined in clinical and preclinical studies, little information is available on the extent to which different hematological subpopula...
Chimeric antigen receptor (CAR) T cell therapy with axicabtagene ciloleucel, tisagenlecleucel and brexucabtagen ciloleucel has been adopted as the standard of care for patients with refractory and/or relapsed CD19‑positive lymphoid malignancies. Monitoring of kinetics of CAR T cells after administration is crucial for patient follow‑up and importan...
Persistence of fetal cells in the circulation of the mother (fetal microchimerism, FM) is associated with increased survival and reduced relapse of children with leukemia receiving a haploidentical hematopoietic stem cell transplantation (hHSCT). NK cells play an important role in maternal tolerance towards the unborn child. In this study, 70 mothe...
Primary myelofibrosis (PMF), post-essential thrombocytemia and post-polycytemia vera myelofibrosis (pET/pPV-MF) are potentially curable with allogeneic stem cell transplantation (allo-SCT). Post-transplant relapse is still a major issue, occurring in a widely variable proportion of patients (22–48%) [1, 2]. Although relapse is still unpredictable,...
CRISPR/Cas9 was described as a bacterial immune system that uses targeted introduction of DNA double-strand breaks (DSBs) to destroy invaders. We hypothesized that we can analogously employ CRISPR/Cas9 nucleases to kill cancer cells by inducing maximal numbers of DSBs in their genome and thus triggering programmed cell death. To do so, we generated...
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Gene therapies have been successfully applied to treat severe inherited and acquired disorders. Although research and development are sufficiently well funded in Germany and while the output of scientific publications and patents is comparable with the leading nations in gene therapy, the country lags noticeably behind with regard to the number of...
Vaccination with the adenoviral-vector based Astra Zeneca ChAdOx1 nCov-19 vaccine is efficient and safe. However, in rare cases vaccinated individuals developed life-threatening thrombotic complications, including thrombosis in cerebral sinus and splanchnic veins. Monitoring of the applied vector in vivo represents an important precondition to stud...
SARS-CoV-2 vaccine ChAdOx1 nCov-19 (AstraZeneca) causes a thromboembolic complication termed vaccine-induced immune thrombotic thrombocytopenia (VITT). Using biophysical techniques, mouse models and analysis of VITT patient samples we identified determinants of this vaccine-induced adverse reaction. Super-resolution microscopy visualized vaccine co...
High-throughput sequencing describes multiple alterations in individual tumors, but their functional relevance is often unclear. Clinic-close, individualized molecular model systems are required for functional validation and to identify therapeutic targets of high significance for each patient. Here, we establish a Cre-ERT2-loxP (causes recombinati...
Ex-vivo gene editing in T lymphocytes paves the way for novel concepts of immunotherapy. One of those strategies is directed at the protection of CD4+-T helper cells from HIV infection in HIV-positive individuals. To this end, we have developed and optimised a CCR5-targeting TALE nuclease, CCR5-Uco-hetTALEN, mediating high-efficiency knockout of C-...
During mammalian pregnancy, immune cells are vertically transferred from mother to fetus. The functional role of these maternal microchimeric cells (MMc) in the offspring is mostly unknown. Here we show a mouse model in which MMc numbers are either normal or low, which enables functional assessment of MMc. We report a functional role of MMc in prom...
Recently, Micklethwaite et al. 1 and Bishop et al. 2 reported results of a phase I first-in-human clinical trial of CD19-directed allogeneic chimeric antigen receptor (CAR)-T cells in 10 patients with relapsed or persistent B cell malignancies after matched-related allogeneic hematopoietic stem cell transplantation (HSCT). CAR-T cells were produced...
Since introduction of CRISPR/Cas9 genome editing has been broadly applied in basic research and applied biotechnology, whereas translation into clinical testing has raised safety concerns. Indeed, although frequencies and locations of off-target events have been widely addressed, little is known about their potential biological consequences in larg...
The Gibbon Ape Leukemia Virus envelope protein (GALV-Env) mediates efficient transduction of human cells, particularly primary B and T lymphocytes, and is therefore of great interest in gene therapy. Using internal domains from murine leukemia viruses (MLV), chimeric GALV-Env proteins such as GALV-C4070A were derived, which allow pseudotyping of le...
Hematotoxicity represents a frequent chimeric antigen receptor (CAR) T-cell related adverse event and remains poorly understood. In this multicenter analysis, we studied patterns of hematopoietic reconstitution and evaluated potential predictive markers in 258 patients receiving Axicabtagene ciloleucel (Axi-cel) or Tisagenlecleucel (Tisa-cel) for r...
Disruption of the C-C-Chemokine-receptor-5 (CCR5) gene induces resistance towards CCR5-tropic HIV. Here we optimised our previously described CCR5-Uco-TALEN and its delivery by mRNA electroporation. The novel variant, CCR5-Uco-hetTALEN features an obligatory heterodimeric Fok1-cleavage domain, which resulted in complete abrogation of off-target act...
Data on the association between chimeric antigen receptor (CAR)-T-cell kinetics and patient outcome in the nontrial setting are missing, mainly due to the lack of broadly available CAR-T-cell diagnostic quantification tools. We performed prospective quantification of axicabtagene ciloleucel (axi-cel) in 21 patients treated for aggressive B-cell lym...
Vaccination with the adenoviral-vector based Astra Zeneca ChAdOx1 nCov-19 vaccine is efficient and safe. However, in rare cases vaccinated individuals developed life-threatening thrombotic complications, including thrombosis in cerebral sinus and splanchnic veins. Monitoring of the applied vector in vivo represents an important precondition to stud...
Electroporation enables the transfection of different cell types including microbial, plant, and animal cells with charged molecules, such as nuclear acids or proteins. During electroporation, an electrical field is applied to the cells leading to a transient permeabilization of the cell membrane allowing exogenous molecules to enter the cells. Her...
We identified a subset of Chronic Lymphocytic Leukemia (CLL) patients with high Signaling Lymphocytic Activation Molecule Family (SLAMF) receptor-related signaling that showed an indolent clinical course. Since SLAMF receptors play a role in NK cell biology, we reasoned that these receptors may impact NK cell-mediated CLL immunity. Indeed, our expe...
Gene therapy can be used to restore cell function in monogenic disorders or to endow cells with new capabilities, such as improved killing of cancer cells, expression of suicide genes for controlled elimination of cell populations, or protection against chemotherapy or viral infection. While gene therapies were originally most often used to treat m...
Dieses essential gibt einen Überblick über Grundlagen sowie Chancen und Risiken der Gentherapie, mit besonderem Fokus auf das Genome Editing. Es werden aktuelle und zukünftige klinische Anwendungen der neuen, mit vielen Hoffnungen, aber auch Ängsten verbundenen Technologien diskutiert.
Der Inhalt
• Grundlagen der somatischen Gentherapie
• Funktion...
Gemäß einer gängigen Definition handelt es sich bei der somatischen Gentherapie um das „Einbringen von Erbinformation in Körperzellen mit dem Ziel, Erkrankungen zu diagnostizieren, zu lindern oder zu heilen“, wobei allerdings Vakzinierungen (Impfungen) mit rekombinanten Nukleinsäuren, wie z. B. aktuell mit den mRNA-basierten Impfstoffen gegen SARS-...
Schon als die Idee der Heilung von Erbkrankheiten durch Korrektur der zugrundeliegenden Gendefekte Mitte der 1960er Jahre entwickelt wurde, schwang auch die eugenische Idee der Verbesserung des menschlichen Erbguts mit. Als man dann in den 1990er Jahren begann, die Idee der Gentherapie praktisch umzusetzen, war man jedoch weit davon entfernt, Gene...
Nachdem es bei den ersten Verfahren des Genome Editing fast 20 Jahre von der Laboranwendung bis zur ersten klinischen Studie gedauert hat, waren es beim CRISPR/Cas-System nur noch ca. 5 Jahre – derzeit laufen bereits Dutzende klinische Studien. Das Genome Editing verspricht durch seine breitere Anwendbarkeit und höhere Genauigkeit gegenüber klassis...
Wie oben erläutert, bestand die ursprüngliche Idee der Gentherapie darin, einen Gendefekt exakt zu reparieren, wofür oft der Begriff der Genchirurgie verwendet wurde. In den letzten Jahren hat sich jedoch der Terminus Genome Editing durchgesetzt, in Analogie zur Korrektur von z. B. Druckfehlern in eigentlich fertigen Texten eines Buches. Wie aber f...
In the ‘Fifth Gene Technology Report’, renowned experts provide an overview of current developments and their applications in the dynamically evolving research field of gene and biotechnologies. They examine, among other topics, genetic diagnostics, somatic gene therapy, the development of vaccines, stem cell and organoid research, green gene techn...
In the ‘Fifth Gene Technology Report’, renowned experts provide an overview of current developments and their applications in the dynamically evolving research field of gene and biotechnologies. They examine, among other topics, genetic diagnostics, somatic gene therapy, the development of vaccines, stem cell and organoid research, green gene techn...
In the ‘Fifth Gene Technology Report’, renowned experts provide an overview of current developments and their applications in the dynamically evolving research field of gene and biotechnologies. They examine, among other topics, genetic diagnostics, somatic gene therapy, the development of vaccines, stem cell and organoid research, green gene techn...
Retroviral insertional mutagenesis (RIM) is both a relevant risk in gene therapy and a powerful tool for identifying genes that enhance the competitiveness of repopulating hematopoietic stem and progenitor cells (HSPCs). However, focusing only on the gene closest to the retroviral vector insertion site (RVIS) may underestimate the effects of RIM, a...
We have recently demonstrated that neural stem cell-based intravitreal co-administration of glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) confers profound protection to injured retinal ganglion cells (RGCs) in a mouse optic nerve crush model, resulting in the survival of ~38% RGCs two months after the ner...
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Besides its broad application in research and biotechnology, genome editing (GE) has great potential for clinical gene therapy, but delivery of GE tools remains a bottleneck. Whereas significant progress has been made in ex vivo GE delivery (e.g., by electroporation), establishment of efficient and safe in vivo delivery systems is still a challenge...
Hematopoietic stem cell transplantation (HSCT) following myeloablative conditioning represents the only curative treatment option to overcome numerous hematologic malignancies. Despite the overall clinical success to achieve reconstitution of the blood system in many patients, the length of the aplastic phase until recovery response remains a criti...
