11 results on '"Hudecek, M."'
Search Results
2. OF CARS AND COMMENSALS - UTILIZING MICROBIOME-DERIVED METABOLITES FOR ENGINEERING AND REPROGRAMMING OF CAR T CELLS TO TREAT SOLID TUMORS
- Author
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Staudt, S., Ziegler-Martin, K., Franz, J., Adil-Gholam, N., Benz, P., Visekruna, A., Huu, P., Ellmeier, W., van den Brink, M., Hudecek, M., and Luu, M.
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- 2024
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3. Next-generation BCMA-targeted chimeric antigen receptor CARTemis-1: the impact of manufacturing procedure on CAR T-cell features.
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Sierro-Martínez B, Escamilla-Gómez V, Pérez-Ortega L, Guijarro-Albaladejo B, Hernández-Díaz P, de la Rosa-Garrido M, Lara-Chica M, Rodríguez-Gil A, Reguera-Ortega JL, Sanoja-Flores L, Arribas-Arribas B, Montiel-Aguilera MÁ, Carmona G, Robles MJ, Caballero-Velázquez T, Briones J, Einsele H, Hudecek M, Pérez-Simón JA, and García-Guerrero E
- Abstract
Purpose: CAR therapy targeting BCMA is under investigation as treatment for multiple myeloma. However, given the lack of plateau in most studies, pursuing more effective alternatives is imperative. We present the preclinical and clinical validation of a new optimized anti-BCMA CAR (CARTemis-1). In addition, we explored how the manufacturing process could impact CAR-T cell product quality and fitness., Methods: CARTemis-1 optimizations were evaluated at the preclinical level both, in vitro and in vivo. CARTemis-1 generation was validated under GMP conditions, studying the dynamics of the immunophenotype from leukapheresis to final product. Here, we studied the impact of the manufacturing process on CAR-T cells to define optimal cell culture protocol and expansion time to increase product fitness., Results: Two different versions of CARTemis-1 with different spacers were compared. The longer version showed increased cytotoxicity. The incorporation of the safety-gene EGFRt into the CARTemis-1 structure can be used as a monitoring marker. CARTemis-1 showed no inhibition by soluble BCMA and presents potent antitumor effects both in vitro and in vivo. Expansion with IL-2 or IL-7/IL-15 was compared, revealing greater proliferation, less differentiation, and less exhaustion with IL-7/IL-15. Three consecutive batches of CARTemis-1 were produced under GMP guidelines meeting all the required specifications. CARTemis-1 cells manufactured under GMP conditions showed increased memory subpopulations, reduced exhaustion markers and selective antitumor efficacy against MM cell lines and primary myeloma cells. The optimal release time points for obtaining the best fit product were > 6 and < 10 days (days 8-10)., Conclusions: CARTemis-1 has been rationally designed to increase antitumor efficacy, overcome sBCMA inhibition, and incorporate the expression of a safety-gene. The generation of CARTemis-1 was successfully validated under GMP standards. A phase I/II clinical trial for patients with multiple myeloma will be conducted (EuCT number 2022-503063-15-00)., (© 2024. The Author(s).)
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- 2024
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4. The Spectrum of CAR Cellular Effectors: Modes of Action in Anti-Tumor Immunity.
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Nguyen NTT, Müller R, Briukhovetska D, Weber J, Feucht J, Künkele A, Hudecek M, and Kobold S
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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. NK cells and γδ T cells that do not need HLA compatibility or macrophages and dendritic cells with additional properties such as phagocytosis or antigen presentation are increasingly seen as cellular vehicles with potential for application. As these cells possess distinct properties, clinicians and researchers need a thorough understanding of their peculiarities and commonalities. This review will compare these different cell types and their specific modes of action seen upon CAR activation.
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- 2024
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5. Breast cancer-on-chip for patient-specific efficacy and safety testing of CAR-T cells.
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Maulana TI, Teufel C, Cipriano M, Roosz J, Lazarevski L, van den Hil FE, Scheller L, Orlova V, Koch A, Hudecek M, Alb M, and Loskill P
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- Humans, Female, Immunotherapy, Adoptive methods, Tumor Microenvironment, T-Lymphocytes immunology, Lab-On-A-Chip Devices, Cell Line, Tumor, Organoids pathology, Breast Neoplasms pathology, Breast Neoplasms immunology, Receptors, Chimeric Antigen metabolism, Receptors, Chimeric Antigen immunology
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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. Additionally, we integrated primary breast cancer organoids to study patient-specific CAR-T cell efficacy. The modular architecture of our tumor-on-chip paves the way for studying the role of other cell types in the TME and thus provides the potential for broad application in bench-to-bedside translation as well as acceleration of the preclinical development of CAR-T cell products., Competing Interests: Declaration of interests M.H. is an inventor on patent applications and has been granted patents related to CAR technology, licensed in part to industry. M.H. is a cofounder and equity owner of T-CURX GmbH, Würzburg. M.H. receives speaker honoraria from BMS, Janssen, Kite/Gilead, and Novartis and research support from BMS., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
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- 2024
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6. Engineering of potent CAR NK cells using non-viral Sleeping Beauty transposition from minimalistic DNA vectors.
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Bexte T, Botezatu L, Miskey C, Gierschek F, Moter A, Wendel P, Reindl LM, Campe J, Villena-Ossa JF, Gebel V, Stein K, Cathomen T, Cremer A, Wels WS, Hudecek M, Ivics Z, and Ullrich E
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- Humans, Animals, Mice, Xenograft Model Antitumor Assays, Transposases genetics, Transposases metabolism, Cell Line, Tumor, DNA Transposable Elements, Cytotoxicity, Immunologic, Precursor Cell Lymphoblastic Leukemia-Lymphoma therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma immunology, Cell Engineering methods, Killer Cells, Natural immunology, Killer Cells, Natural metabolism, Genetic Vectors genetics, Receptors, Chimeric Antigen genetics, Receptors, Chimeric Antigen immunology, Receptors, Chimeric Antigen metabolism, Immunotherapy, Adoptive methods
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Natural killer (NK) cells have high intrinsic cytotoxic capacity, and clinical trials have demonstrated their safety and efficacy for adoptive cancer therapy. Expression of chimeric antigen receptors (CARs) enhances NK cell target specificity, with these cells applicable as off-the-shelf products generated from allogeneic donors. Here, we present for the first time an innovative approach for CAR NK cell engineering employing a non-viral Sleeping Beauty (SB) transposon/transposase-based system and minimized DNA vectors termed minicircles. SB-modified peripheral blood-derived primary NK cells displayed high and stable CAR expression and more frequent vector integration into genomic safe harbors than lentiviral vectors. Importantly, SB-generated CAR NK cells demonstrated enhanced cytotoxicity compared with non-transfected NK cells. A strong antileukemic potential was confirmed using established acute lymphocytic leukemia cells and patient-derived primary acute B cell leukemia and lymphoma samples as targets in vitro and in vivo in a xenograft leukemia mouse model. Our data suggest that the SB-transposon system is an efficient, safe, and cost-effective approach to non-viral engineering of highly functional CAR NK cells, which may be suitable for cancer immunotherapy of leukemia as well as many other malignancies., Competing Interests: Declaration of interests E.U. is an Advisory Board member for Phialogics and has sponsored research projects with Gilead and BMS. Z.I. is an inventor on patents related to Sleeping Beauty and MC technology. M.H. is listed as inventor on patent applications and granted patents related to CAR technologies and transposon-based gene transfer that are, in part licensed to industry. M.H. is a co-founder and equity owner of T-CURX GmbH, Würzburg, Germany. M.H. and E.U. are inventors on patents related to CAR and MC technology. T.B., P.W., W.S.W., and E.U. are inventors on patents related to optimized CAR designs. T.B., P.W., and E.U. are inventors on non-viral gene-editing technologies of NK cells., (Copyright © 2024. Published by Elsevier Inc.)
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- 2024
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7. Correction: ROR1-targeting switchable CAR-T cells for cancer therapy.
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Peng H, Nerreter T, Mestermann K, Wachter J, Chang J, Hudecek M, and Rader C
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- 2024
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8. Mutation-specific CAR T cells as precision therapy for IGLV3-21 R110 expressing high-risk chronic lymphocytic leukemia.
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Märkl F, Schultheiß C, Ali M, Chen SS, Zintchenko M, Egli L, Mietz J, Chijioke O, Paschold L, Spajic S, Holtermann A, Dörr J, Stock S, Zingg A, Läubli H, Piseddu I, Anz D, Minden MD, Zhang T, Nerreter T, Hudecek M, Minguet S, Chiorazzi N, Kobold S, and Binder M
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- Humans, Female, Mice, Animals, B-Lymphocytes, Mutation, Receptors, Antigen, B-Cell genetics, T-Lymphocytes, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell therapy
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The concept of precision cell therapy targeting tumor-specific mutations is appealing but requires surface-exposed neoepitopes, which is a rarity in cancer. B cell receptors (BCR) of mature lymphoid malignancies are exceptional in that they harbor tumor-specific-stereotyped sequences in the form of point mutations that drive self-engagement of the BCR and autologous signaling. Here, we use a BCR light chain neoepitope defined by a characteristic point mutation (IGLV3-21
R110 ) for selective targeting of a poor-risk subset of chronic lymphocytic leukemia (CLL) with chimeric antigen receptor (CAR) T cells. We develop murine and humanized CAR constructs expressed in T cells from healthy donors and CLL patients that eradicate IGLV3-21R110 expressing cell lines and primary CLL cells, but neither cells expressing the non-pathogenic IGLV3-21G110 light chain nor polyclonal healthy B cells. In vivo experiments confirm epitope-selective cytolysis in xenograft models in female mice using engrafted IGLV3-21R110 expressing cell lines or primary CLL cells. We further demonstrate in two humanized mouse models lack of cytotoxicity towards human B cells. These data provide the basis for advanced approaches of resistance-preventive and biomarker-guided cellular targeting of functionally relevant lymphoma driver mutations sparing normal B cells., (© 2024. The Author(s).)- Published
- 2024
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9. BCMA CAR-T cells in multiple myeloma-ready for take-off?
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Scheller L, Tebuka E, Rambau PF, Einsele H, Hudecek M, Prommersberger SR, and Danhof S
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- Humans, B-Cell Maturation Antigen, Immunotherapy, Adoptive methods, T-Lymphocytes, Multiple Myeloma therapy, Receptors, Chimeric Antigen
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Although the approval of new drugs has improved the clinical outcome of multiple myeloma (MM), it was widely regarded as incurable over the past decades. However, recent advancements in groundbreaking immunotherapies, such as chimeric antigen receptor T cells (CAR-T), have yielded remarkable results in heavily pretreated relapse/refractory patients, instilling hope for a potential cure. CAR-T are genetically modified cells armed with a novel receptor to specifically recognize and kill tumor cells. Among the potential targets for MM, the B-cell maturation antigen (BCMA) stands out since it is highly and almost exclusively expressed on plasma cells. Here, we review the currently approved BCMA-directed CAR-T products and ongoing clinical trials in MM. Furthermore, we explore innovative approaches to enhance BCMA-directed CAR-T and overcome potential reasons for treatment failure. Additionally, we explore the side effects associated with these novel therapies and shed light on accessibility of CAR-T therapy around the world.
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- 2024
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10. CAR T-cell therapy in multiple myeloma: mission accomplished?
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Rasche L, Hudecek M, and Einsele H
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- Humans, Immunotherapy, Adoptive, B-Cell Maturation Antigen metabolism, Antilymphocyte Serum, Multiple Myeloma therapy, Receptors, Chimeric Antigen
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Abstract: B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body of clinical and correlative preclinical data that support their inclusion into firstline therapy and sequencing before T-cell-engaging antibodies. The ambition to cure MM with (BCMA-)CAR T cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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11. Trust in and Acceptance of Artificial Intelligence Applications in Medicine: Mixed Methods Study.
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Shevtsova D, Ahmed A, Boot IWA, Sanges C, Hudecek M, Jacobs JJL, Hort S, and Vrijhoef HJM
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- Humans, Educational Status, Artificial Intelligence, Trust, Medicine
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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., Objective: The aim of this study was to identify factors related to trust in and acceptance of novel AI-powered medical technologies and to assess the relevance of those factors among relevant stakeholders., Methods: This study used a mixed methods design. First, a rapid review of the existing literature was conducted, aiming to identify various factors related to trust in and acceptance of novel AI applications in medicine. Next, an electronic survey including the rapid review-derived factors was disseminated among key stakeholder groups. Participants (N=22) were asked to assess on a 5-point Likert scale (1=irrelevant to 5=relevant) to what extent they thought the various factors (N=19) were relevant to trust in and acceptance of novel AI applications in medicine., Results: The rapid review (N=32 papers) yielded 110 factors related to trust and 77 factors related to acceptance toward AI technology in medicine. Closely related factors were assigned to 1 of the 19 overarching umbrella factors, which were further grouped into 4 categories: human-related (ie, the type of institution AI professionals originate from), technology-related (ie, the explainability and transparency of AI application processes and outcomes), ethical and legal (ie, data use transparency), and additional factors (ie, AI applications being environment friendly). The categorized 19 umbrella factors were presented as survey statements, which were evaluated by relevant stakeholders. Survey participants (N=22) represented researchers (n=18, 82%), technology providers (n=5, 23%), hospital staff (n=3, 14%), and policy makers (n=3, 14%). Of the 19 factors, 16 (84%) human-related, technology-related, ethical and legal, and additional factors were considered to be of high relevance to trust in and acceptance of novel AI applications in medicine. The patient's gender, age, and education level were found to be of low relevance (3/19, 16%)., Conclusions: The results of this study could help the implementers of medical AI applications to understand what drives trust and acceptance toward AI-powered technologies among key stakeholders in medicine. Consequently, this would allow the implementers to identify strategies that facilitate trust in and acceptance of medical AI applications among key stakeholders and potential users., (©Daria Shevtsova, Anam Ahmed, Iris W A Boot, Carmen Sanges, Michael Hudecek, John J L Jacobs, Simon Hort, Hubertus J M Vrijhoef. Originally published in JMIR Human Factors (https://humanfactors.jmir.org), 17.01.2024.)
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- 2024
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