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Transcriptional states of CAR-T infusion relate to neurotoxicity: lessons from high-resolution single-cell SOM expression portrayingLoeffler-Wirth, Henry, Rade, Michael, Arakelyan, Arsen, Kreuz, Markus, Loeffler, Markus, Koehl, Ulrike, Reiche, Kristin, Binder, Hans 04 March 2024 (has links)
Anti-CD19 CAR-T cell immunotherapy is a hopeful treatment option for
patients with B cell lymphomas, however it copes with partly severe adverse
effects like neurotoxicity. Single-cell resolved molecular data sets in
combination with clinical parametrization allow for comprehensive
characterization of cellular subpopulations, their transcriptomic states, and
their relation to the adverse effects. We here present a re-analysis of single-cell
RNA sequencing data of 24 patients comprising more than 130,000 cells with
focus on cellular states and their association to immune cell related
neurotoxicity. For this, we developed a single-cell data portraying workflow
to disentangle the transcriptional state space with single-cell resolution and its
analysis in terms of modularly-composed cellular programs. We demonstrated
capabilities of single-cell data portraying to disentangle transcriptional states
using intuitive visualization, functional mining, molecular cell stratification, and
variability analyses. Our analysis revealed that the T cell composition of the
patient’s infusion product as well as the spectrum of their transcriptional states
of cells derived from patients with low ICANS grade do not markedly differ from
those of cells from high ICANS patients, while the relative abundancies,
particularly that of cycling cells, of LAG3-mediated exhaustion and of CAR
positive cells, vary. Our study provides molecular details of the transcriptomic
landscape with possible impact to overcome neurotoxicity.
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Computational Network Mining in High-Risk Patients with Multiple MyelomaYu, Christina Y. January 2020 (has links)
No description available.
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Cellular immunotherapy of pancreatic ductal adenocarcinoma: Discovery and evaluation of novel target candidatesSchäfer, Daniel 26 March 2021 (has links)
No description available.
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Influence of Culture Conditions on Ex Vivo Expansion of T Lymphocytes and Their Function for Therapy: Current Insights and Open QuestionsSudarsanam, Harish, Buhmann, Raymund, Henschler, Reinhard 20 October 2023 (has links)
Ex vivo expansion of T lymphocytes is a central process in the generation of cellular therapies
targeted at tumors and other disease-relevant structures,which currently cannot be reached by
established pharmaceuticals. The influence of culture conditions on T cell functions is, however,
incompletely understood. In clinical applications of ex vivo expanded T cells, so far, a relatively
classical standard cell culture methodology has been established. The expanded cells have
been characterized in both preclinical models and clinical studies mainly using a therapeutic
endpoint, for example antitumor response and cytotoxic function against cellular targets,
whereas the influence of manipulations of T cells ex vivo including transduction and culture
expansion has been studied to a much lesser detail, or in many contexts remains unknown.
This includes the circulation behavior of expanded T cells after intravenous application, their
intracellular metabolism and signal transduction, and their cytoskeletal (re)organization or their
adhesion, migration, and subsequent intra-tissue differentiation. This review aims to provide an
overview of established T cell expansion methodologies and address unanswered questions
relating in vivo interaction of ex vivo expanded T cells for cellular therapy.
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Targeting B non-Hodgkin lymphoma and tumor-supportive follicular helper T cells with anti-CXCR5 CAR T cellsPfeilschifter, Janina Marie 09 September 2021 (has links)
CAR-T-Zell-Therapie ist eine vielversprechende neuartige Behandlungsform für Patienten mit aggressiven B-Zell Non-Hodgkin-Lymphomen (B-NHL). In dieser Arbeit wurde die anti-CXCR5 CAR-T-Zell-Therapie als Alternative zur anti-CD19 CAR-T-Zell-Therapie für die Behandlung von reifen B-NHLs untersucht. CXCR5 ist ein B-Zell-homing Rezeptor, der von reifen B Zellen und follikulären T-Helferzellen (TFH Zellen) exprimiert wird. TFH Zellen wurden als tumor-unterstützend in chronisch lymphatischer Leukämie (CLL) und im follikulären Lymphom (FL) beschrieben. Dieses Expressionsmuster erlaubt es, auf einzigartige Weise zeitgleich die malignen Zellen und die tumorunterstützende Mikroumgebung mithilfe von CAR-T-Zell-Therapie gerichtet gegen einen Chemokinrezeptor anzugreifen. Die wichtigsten Ergebnisse dieser Arbeit waren, dass (1) die anti-CXCR5 CAR T-Zellen zielgerichtet CXCR5 positive reife B-NHL Zelllinien und Patientenproben in vitro eliminierten und eine starke anti-Tumor Reaktivität in einem immundefizienten Xenotransplantationsmausmodell zeigten, (2) die anti-CXCR5 CAR T-Zellen zielgerichtet die tumorunterstützenden TFH Zellen in CLL und FL Patientenproben in vitro erkannten und dass (3) CXCR5 ein sicheres Expressionsprofil zeigte. CXCR5 war stark und häufig auf B-NHL exprimiert und die Expression auf gesundem Gewebe war auf lymphoide Zellen beschränkt. Zusammenfassend lässt sich sagen, dass die anti-CXCR5 CAR-T-Zell-Therapie eine neue Behandlungsmöglichkeit für Patienten mit reifen B-NHL darstellt, indem durch die anti-CXCR5 CAR-T Zellen sowohl der Tumor als auch ein Anteil der tumorunterstützende Mikroumgebung eliminiert werden.
Im zweiten Teil der Arbeit wurde das Eμ-Tcl1 murine CLL Lymphommodell genutzt um die Auswirkung der Lymphomentwicklung auf die CXCR5+ T Zellen zu untersuchen. Mittels RNA-Einzelzell-Sequenzierung konnte ein profunder Einfluss des Lymphomwachstums auf das T Zell-Kompartiment der Mäuse, denen Eμ-Tcl1 Zellen gespritzt wurden, gezeigt werden. / CAR T cell therapy is a promising new treatment option for patients suffering from aggressive B non-Hodgkin lymphomas (NHLs). In CAR T cell therapy, patient-derived T cells are genetically modified to express a chimeric receptor commonly directed towards a surface antigen expressed by neoplastic cells. In this thesis, anti-CXCR5 CAR T cell therapy was investigated as an alternative to anti-CD19 CAR T cell therapy for the treatment of mature B-NHLs. CXCR5 is a B cell homing receptor expressed by mature B cells and follicular helper T (TFH) cells. TFH cells were described to support the tumor cells in chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL). This expression pattern allows simultaneous targeting of the malignant cells and the tumor-supporting microenvironment by CAR T cell therapy against a chemokine receptor in an unprecedented manner. Main findings included that (1) anti-CXCR5 CAR T cells targeted specifically CXCR5 expressing mature B-NHL cell lines and patient samples in vitro and showed strong in vivo anti-tumor reactivity in an immunodeficient xenograft mouse model, (2) anti-CXCR5 CAR T cells targeted tumor-supportive TFH cells derived from CLL and FL patient samples in vitro and (3) CXCR5 showed a safe expression profile. CXCR5 was strongly and frequently expressed by B-NHLs and its expression on healthy tissue was restricted to lymphoid cells. In summary, anti-CXCR5 CAR T cell therapy presents a novel treatment option for patients suffering from mature B-NHLs by eliminating the tumor and part of the tumor-supportive microenvironment.
The second part of the project, the Eμ-Tcl1 murine lymphoma model, which mimics human CLL, was used to study the impact of lymphomagenesis on CXCR5+ T cells. Using single cell RNA sequencing, a profound influence of lymphoma growth on the T cell compartment in Eμ-Tcl1 tumor-challenged mice could be shown.
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Improving NK and T Cell Immunotherapies for Hematologic MalignanciesWong, Derek Perseus 26 May 2023 (has links)
No description available.
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