Publications by authors named "Hudecek M"

Antibody-mediated rejection (AMR) remains a major complication after solid organ transplantation (SOT). Current treatment options are inefficient and result in drastic impairment of the general immunity. To selectively eliminate responsible alloreactive B cells characterized by anti-donor-HLA B cell receptors (BCRs), we generated T cells overcoming rejection by antibodies (CORA-Ts) engineered with a novel chimeric receptor comprising a truncated donor-HLA molecule as antigen recognition domain.

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Background: Chimeric antigen receptor (CAR)-T cell therapy has emerged as a transformative modality in the treatment of patients with cancer. However, it is increasingly evident that this therapeutic approach is not without its challenges. The unique nature of CAR-T cells as living drugs introduces a distinct set of side effects.

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Precision, or personalised medicine has advanced requirements for medical data management systems (MedDMSs). MedDMS for precision medicine should be able to process hundreds of parameters from multiple sites, be adaptable while remaining in sync at multiple locations, real-time syncing to analytics and be compliant with international privacy legislation. This paper describes the LogiqSuite software solution, aimed to support a precision medicine solution at the patient care (LogiqCare), research (LogiqScience) and data science (LogiqAnalytics) level.

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The successful application of CAR-T cells in the treatment of hematologic malignancies has fundamentally changed cancer therapy. With increasing numbers of registered CAR-T cell clinical trials, efforts are being made to streamline and reduce the costs of CAR-T cell manufacturing while improving their safety. To date, all approved CAR-T cell products have relied on viral-based gene delivery and genomic integration methods.

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The success of cellular immunotherapies such as chimeric antigen receptor (CAR) T cell therapy has led to their implementation as a revolutionary treatment option for cancer patients. However, the safe translation of such novel immunotherapies, from non-clinical assessment to first-in-human studies is still hampered by the lack of suitable and models recapitulating the complexity of the human immune system. Additionally, using cells derived from human healthy volunteers in such test systems may not adequately reflect the altered state of the patient's immune system thus potentially underestimating the risk of life-threatening conditions, such as cytokine release syndrome (CRS) following CAR T cell therapy.

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CD19-targeted chimeric antigen receptor-modified T (CAR-T) cells have shown success in clinical studies, with several CD19 CAR-T cell products now having been approved for market use. However, this cell therapy can be associated with side effects such as cytokine release syndrome (CRS). Therefore, pre-clinical test systems are highly desired to permit the evaluation of these unwanted effects before clinical trials begin.

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Multiple myeloma (MM) treatment remains challenging due to its relapsed/refractory disease course as well as intra- and inter-patient heterogeneity. Cellular immunotherapies, especially chimeric antigen receptor (CAR)-T cells targeting B cell maturation antigen (BCMA), mark a major breakthrough, achieving long-lasting remissions and instilling hope for a potential cure. While ongoing clinical trials are increasingly driving approved cellular products towards earlier lines of therapy, novel targets as well as advanced approaches employing natural killer (NK) cells or dendritic cell (DC) vaccines are currently under investigation.

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Chimeric antigen receptor T-cell therapies have markedly improved the survival rates of patients with B-cell malignancies. However, their efficacy in other hematological cancers, such as acute myeloid leukemia, and in solid tumors has been limited. Key obstacles include the downregulation or loss of antigen expression on cancer cells, restricted accessibility to target cells, and the poor persistence of these "living drugs" because of the highly immunosuppressive tumor microenvironment.

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Chimeric antigen receptor (CAR)-T cell products, classified as Advanced Therapy Medicinal Products (ATMPs), have shown promising outcomes in cancer immunotherapy. The quality of raw and starting materials used in manufacturing is critical to ensure the efficacy and safety of CAR-T cell products and depends primarily on the selection of the right materials and the right suppliers. It is essential to consider a long-term strategy when selecting raw and starting materials to prevent delays in the supply of innovative, high-quality, and safe therapies to patients.

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Chimeric antigen receptor (CAR)-based cell therapies have shown impressive efficacy in the treatment of hematological malignancies. Recently, these therapies are being developed for infectious diseases, yet studies targeting fungal infections remain scarce. To identify optimal targets and optimize cellular products, we developed a method to engineer chimeric antigen receptor-natural killer (CAR-NK) cells and evaluated their response to stimulation by fungi.

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Article Synopsis
  • Research shows a correlation between the gut microbiome and the effectiveness of cancer immunotherapy, specifically for CAR T cell patients.
  • The study identifies pentanoate, a metabolite from commensal bacteria, as a key factor that enhances patient survival by improving CAR T cell performance in challenging tumor environments.
  • Findings suggest that incorporating microbial metabolites like pentanoate into CAR T cell manufacturing can exploit metabolic pathways and epigenetic changes to enhance treatment outcomes.
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Low antigen sensitivity and a gradual loss of effector functions limit the clinical applicability of chimeric antigen receptor (CAR)-modified T cells and call for alternative antigen receptor designs for effective T cell-based cancer immunotherapy. Here, we applied advanced microscopy to demonstrate that TCR/CD3-based synthetic constructs (TCC) outperform second-generation CAR formats with regard to conveyed antigen sensitivities by up to a thousandfold. TCC-based antigen recognition occurred without adverse nonspecific signaling, which is typically observed in CAR-T cells, and did not depend-unlike sensitized peptide/MHC detection by conventional T cells-on CD4 or CD8 coreceptor engagement.

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Article Synopsis
  • CAR therapy targeting BCMA is being improved with the new anti-BCMA CAR called CARTemis-1, which aims to be more effective against multiple myeloma, addressing the challenges of current treatments that lack sustained effectiveness.
  • The study demonstrated that the longer version of CARTemis-1 showed better cancer-killing ability and confirmed that certain manufacturing conditions, like specific cytokines, enhance CAR-T cell quality and effectiveness.
  • CARTemis-1 was found to be effective without being inhibited by soluble BCMA, and it successfully met regulatory standards for production while exhibiting strong antitumor effects in both lab and live models.
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Chimeric antigen receptor-T cells have spearheaded the field of adoptive cell therapy and have shown remarkable results in treating hematological neoplasia. Because of the different biology of solid tumors compared to hematological tumors, response rates of CAR-T cells could not be transferred to solid entities yet. CAR engineering has added co-stimulatory domains, transgenic cytokines and switch receptors to improve performance and persistence in a hostile tumor microenvironment, but because of the inherent cell type limitations of CAR-T cells, including HLA incompatibility, toxicities (cytokine release syndrome, neurotoxicity) and high costs due to the logistically challenging preparation process for autologous cells, the use of alternative immune cells is gaining traction.

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Background: Artificial intelligence (AI) is often promoted as a potential solution for many challenges health care systems face worldwide. However, its implementation in clinical practice lags behind its technological development.

Objective: This study aims to gain insights into the current state and prospects of AI technology from the stakeholders most directly involved in its adoption in the health care sector whose perspectives have received limited attention in research to date.

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Physiologically relevant human models that recapitulate the challenges of solid tumors and the tumor microenvironment (TME) are highly desired in the chimeric antigen receptor (CAR)-T cell field. We developed a breast cancer-on-chip model with an integrated endothelial barrier that enables the transmigration of perfused immune cells, their infiltration into the tumor, and concomitant monitoring of cytokine release during perfused culture over a period of up to 8 days. Here, we exemplified its use for investigating CAR-T cell efficacy and the ability to control the immune reaction with a pharmacological on/off switch.

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Article Synopsis
  • NK cells are powerful immune cells with proven effectiveness in cancer therapy, especially when enhanced by CAR technology, allowing them to target cancer cells more specifically.
  • The study introduces a novel non-viral method using the Sleeping Beauty transposon system and minicircles to engineer CAR NK cells, resulting in stable CAR expression and improved genetic integration compared to traditional methods.
  • These engineered CAR NK cells showed greater effectiveness against leukemia cells in lab models, suggesting a promising avenue for developing cost-effective and safe cancer immunotherapies.
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Despite the rise of decision support systems enabled by artificial intelligence (AI) in personnel selection, their impact on decision-making processes is largely unknown. Consequently, we conducted five experiments (N = 1403 students and Human Resource Management (HRM) employees) investigating how people interact with AI-generated advice in a personnel selection task. In all pre-registered experiments, we presented correct and incorrect advice.

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Article Synopsis
  • The study explores targeting tumor-specific mutations in cancer through precision cell therapy, focusing on B cell receptors (BCR) that have unique mutations in chronic lymphocytic leukemia (CLL).
  • Researchers developed chimeric antigen receptor (CAR) T cells that specifically target a neoepitope defined by a notable mutation (IGLV3-21), successfully eradicating cancer cells without harming healthy B cells.
  • In vivo experiments using mouse models confirmed that the CAR T cells selectively destroy malignant cells expressing the IGLV3-21 mutation while safeguarding normal B cells, suggesting a promising approach for treating CLL.
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Background: Artificial intelligence (AI)-powered technologies are being increasingly used in almost all fields, including medicine. However, to successfully implement medical AI applications, ensuring trust and acceptance toward such technologies is crucial for their successful spread and timely adoption worldwide. Although AI applications in medicine provide advantages to the current health care system, there are also various associated challenges regarding, for instance, data privacy, accountability, and equity and fairness, which could hinder medical AI application implementation.

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Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections.

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The treatment landscape in multiple myeloma (MM) is shifting from genotoxic drugs to immunotherapies. Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood.

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Article Synopsis
  • To speed up the creation of Advanced Therapy Medicinal Products (ATMPs) for patients with serious cancers, regulatory strategies must be regularly reviewed and adapted, focusing on balancing risk with early clinical research.
  • The T2EVOLVE consortium is exploring ways to fast-track CAR and TCR-engineered T cell therapies in the EU by using existing regulatory tools to support an adaptable learning process for different product versions.
  • As knowledge about the connections between product quality, manufacturing, clinical effectiveness, and safety increases, there are emerging opportunities to simplify regulatory submissions and clinical studies, potentially applying these insights to other engineered cell therapies like CAR NK cell products.
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