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"Wilhelm, Martin"
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Improving the Efficiency of Vγ9Vδ2 T-Cell Immunotherapy in Cancer
Increasing immunological knowledge and advances in techniques lay the ground for more efficient and broader application of immunotherapies. gamma delta (γδ) T-cells possess multiple favorable anti-tumor characteristics, making them promising candidates to be used in cellular and combination therapies of cancer. They recognize malignant cells, infiltrate tumors, and depict strong cytotoxic and pro-inflammatory activity. Here, we focus on human Vγ9Vδ2 T-cells, the most abundant γδ T-cell subpopulation in the blood, which are able to inhibit cancer progression in various models
and
. For therapeutic use they can be cultured and manipulated
and in the following adoptively transferred to patients, as well as directly stimulated to propagate
. In clinical studies, Vγ9Vδ2 T-cells repeatedly demonstrated a low toxicity profile but hitherto only the modest therapeutic efficacy. This review provides a comprehensive summary of established and newer strategies for the enhancement of Vγ9Vδ2 T-cell anti-tumor functions. We discuss data of studies exploring methods for the sensitization of malignant cells, the improvement of recognition mechanisms and cytotoxic activity of Vγ9Vδ2 T-cells. Main aspects are the tumor cell metabolism, antibody-dependent cell-mediated cytotoxicity, antibody constructs, as well as activating and inhibitory receptors like NKG2D and immune checkpoint molecules. Several concepts show promising results
, now awaiting translation to
models and clinical studies. Given the array of research and encouraging findings in this area, this review aims at optimizing future investigations, specifically targeting the unanswered questions.
Journal Article
Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with haematological malignancies: an open-label, multicentre, randomised study
Routine prophylactic platelet transfusion is the standard of care for patients with severe thrombocytopenia. We assessed the effect of a new strategy of therapeutic platelet transfusion on the number of transfusions and safety in patients with hypoproliferative thrombocytopenia.
We did a multicentre, open-label, randomised parallel-group trial at eight haematology centres in Germany. Patients aged 16–80 years, who were undergoing intensive chemotherapy for acute myeloid leukaemia or autologous haemopoietic stem-cell transplantation for haematological cancers, were randomly assigned via a computer-generated randomisation sequence to receive either platelet transfusion when bleeding occurred (therapeutic strategy) or when morning platelet counts were 10×109 per L or lower (prophylactic strategy). Investigators undertaking interventions were not masked to group assignment. The primary endpoint was the number of platelet transfusions. Analysis was by intention to treat. This trial is registered, NCT00521664.
197 patients were assigned the prophylactic strategy and 199 the therapeutic strategy. Of 391 patients analysed, the therapeutic strategy reduced the mean number of platelet transfusions by 33·5% (95% CI 22·2–43·1; p<0·0001) in all patients (2·44 [2·22–2·67] in prophylactic group vs 1·63 [1·42–1·83] in therapeutic group), 31·6% (18·6–42·6; p<0·0001) in those with acute myeloid leukaemia (2·68 [2·35–3·01] vs 1·83 [1·58–2·10]), and 34·2% (6·6–53·7; p=0·0193) in those who had had autologous transplantation (1·80 [1·45–2·15] vs 1·18 [0·82–1·55]. We noted no increased risk of major haemorrhage in patients who had undergone autologous transplantation. In those with acute myeloid leukaemia, risk of non-fatal grade 4 (mostly CNS) bleeding was increased. We recorded 15 cases of non-fatal haemorrhage: four retinal in each transfusion group, and one vaginal and six cerebral in the therapeutic group. 12 patients died in the study: two from fatal cerebral haemorrhages in the therapeutic group, and ten (five in each treatment group) unrelated to major bleeding.
The therapeutic strategy could become a new standard of care after autologous stem-cell transplantation; however, prophylactic platelet transfusion should remain the standard for patients with acute myeloid leukaemia. The new strategy should be used by some haematology centres only if the staff are well educated and experienced in the new approach and can react in a timely way to first signs of CNS bleeding.
Deutsche Krebshilfe eV (German Cancer Aid).
Journal Article
Hans in luck : seven stories
\"Felix Hoffmann--one of Switzerland's most important children's book illustrators of the twentieth century--brings wonder and intrigue to these classic Brothers Grimm fairy tales ... Hoffman's subtle details and keen ability to portray expression in humans and animals alike make this collection a visual treaure, and one to explore again and again.\"--Book jacket front flap.
Book
Linear Computation Coding: A Framework for Joint Quantization and Computing
Here we introduce the new concept of computation coding. Similar to how rate-distortion theory is concerned with the lossy compression of data, computation coding deals with the lossy computation of functions. Particularizing to linear functions, we present an algorithmic approach to reduce the computational cost of multiplying a constant matrix with a variable vector, which requires neither a matrix nor vector having any particular structure or statistical properties. The algorithm decomposes the constant matrix into the product of codebook and wiring matrices whose entries are either zero or signed integer powers of two. For a typical application like the implementation of a deep neural network, the proposed algorithm reduces the number of required addition units several times. To achieve the accuracy of 16-bit signed integer arithmetic for 4k-vectors, no multipliers and only 1.5 adders per matrix entry are needed.
Journal Article
الأنتولوجيا : (تأويليات الحدثية) : (من دروس فرايبورغ الأولى لسداسي الصيف 1923)
يتناول كتاب (الأنتولوجيا : (تأويليات الحدثية) : (من دروس فرايبورغ الأولى لسداسي الصيف 1923)) والذي قام بتأليفه (مارتن هيدغر) ويقع في حوالي (342) صفحة من القطع المتوسط موضوع (علم الوجود) مستعرضا المحتويات التالية : القسم الأول : دروب تفسير الموجد في وهلية مريته، القسم الثاني : السبيل الفينومينولوجية إلى هرمينوتيقا الحديثة.
Book
An optimized cultivation method for future in vivo application of γδ T cells
γδ T cells, with their properties of both the innate and acquired immune systems, are suitable candidates for cellular immunotherapy in cancer. Because of their non-major histocompatibility complex (MHC) binding T cell receptor, allogenic transfer is feasible without relevant graft versus host reactions. In recent years, much experience has been gained with ex vivo expansion and stimulation of γδ T cells using bisphosphonates and Interleukin 2. Unfortunately, many current stimulation protocols are based on the use of xenogenic materials and other potentially hazardous supplements, which conflicts with basic principles of Good Manufacturing Practice (GMP). Adherence to the concept and current guidelines of GMP is state of the art for production of Advanced Therapy Medicinal Products (ATMP) like cell therapeutics and a necessity for clinical use under a regulatory perspective. In this study, we developed a new stimulation protocol that induces a marked increase of γδ T cell counts and allows for an easier transition from research to clinical applications with minimized regulatory workload. It reliably leads to a cell product with a purity of more than 90% γδ T cells and improved in vitro anti-tumor activity compared to our previous standard procedure. Furthermore, by investigating correlations between properties of unstimulated γδ T cells and proliferation rate as well as degranulation ability of stimulated γδ T cells, we can draw conclusions about suitable donors. Finally, we examined if expansion can be improved by pulsing zoledronate and/or using Interleukin 15 with or without Interleukin 2. Significant improvements can be achieved with respect to intrinsic and antibody-dependent cell-mediated cytotoxicity. Our results demonstrate that the stimulation protocol presented here leads to an improved γδ T cell product for future clinical applications.
Journal Article
Characterization of Stimulated γδ T Cells: Phenotypic Analysis and Implications for Allogeneic Cellular Immunotherapy
Due to their anti-tumor activity and non-major histocompatibility complex (MHC) binding T cell receptor, γδ T cells are suitable candidates for allogeneic cellular immunotherapy in cancer. Recently, we developed a new protocol called Ko-Op for stimulation of γδ T cells (specifically Vy9Vδ2 T cells) that generates a cell product consisting mainly of γδ T cells with preserved anti-tumor activity targeted for clinical-grade application. In this study, we investigated the phenotype of stimulated γδ T cells and correlated this with results of functional assays to obtain a deeper understanding of the characteristics of stimulated γδ T cells. Additionally, an intensive analysis of surface molecules of unstimulated and stimulated γδ T cells is presented. Since heterogeneous results regarding the response to therapy with γδ T cells observed in earlier clinical trials could be a consequence of various extents of γδ T cell adhesion and migration ability, we addressed surface molecules associated with cellular activity and adhesion and migration functions as well. By investigating correlations between the phenotype of unstimulated γδ T cells and cellular cytotoxicity, as well as the degranulation ability of stimulated γδ T cells, we could draw conclusions about optimal donors for further allogeneic cellular therapies. Finally, we demonstrated that the phenotype varies over the time of culture and is clearly modifiable by changing the stimulation protocol.
Journal Article
Engaging anaesthesia professionals as co-faculty in stroke thrombectomy simulation training: associations with clinical care and patient outcomes
Background
Simulation-based training for endovascular thrombectomy (EVT) may improve care for patients with acute ischaemic stroke. This study investigated whether engaging anaesthesia professionals as co-faculty in an established in situ simulation programme influenced EVT care and patient outcomes.
Methods
This single centre pre-post interventional study (2017-2023) evaluated the impact of revising an EVT simulation training programme by engaging anaesthesia professionals in its design, delivery, and debriefing. Outcomes were measured by changes in: (1) anaesthetic management (relative and absolute time systolic blood pressure was outside protocol thresholds, hypoxic time, and protocol adherence), (2) workflow process (time metrics, successful revascularisation rates, and intraprocedural complications), and (3) patient outcomes (intracerebral haemorrhage, National Institute of Health Stroke Scale scores and modified Rankin Scale scores).
Results
A total of 275 stroke patients were treated with EVT during the study period (189 pre- and 86 postintervention). Anaesthetic management improved significantly in the postintervention group, with a decrease in the proportion of time that systolic blood pressure remained outside thresholds (37.0% to 27.7%,
p
= 0.02), increased compliance with recommended anaesthetics (27.5% to 100.0%,
p
< 0.001), and a reduction in hypoxia (5 to 0 min,
p
< 0.001). Time from suite arrival to groin puncture increased from 15 to 20 min in the postintervention group (
p
= 0.003). No significant differences were observed between the groups in the remaining workflow time metrics, reperfusion rates, or procedural complications. The proportion of patients with an excellent outcome (modified Rankin Scale 0–1) improved significantly from 23.4% to 42.6% in the postintervention group (
p
= 0.01).
Conclusions
The engagement of anaesthesia professionals in the EVT simulation training faculty was associated with improved EVT anaesthesia care and improved patient outcomes. The multidisciplinary nature of the EVT team should be reflected in faculty composition for EVT simulation training.
Journal Article