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Kombinace nádorové imunoterapie s blokací inhibitorů apoptózy
HAVLOVÁ, Aneta
The aim of this thesis was to study the possibility of combination of cancer immunotherapy with blockade of inhibitors of apoptosis. I described structure, functions, and the effect of these inhibitors on cancer development. Special attention was paid to the ways which can be used to block inhibitors of apoptosis. Finally I suggested the combination of blockade of these inhibitors with MBTA immunotherapy.
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Imunoterapie metastazujícího pankreatického adenokarcinomu řešená na dvounádorovém modelu
SKALIČKOVÁ, Markéta
This master's thesis studies the efficacy of cancer immunotherapy based on TLR agonists and ligands stimulating phagocytosis, abbreviated as MBTA therapy, using a mouse model of pancreatic adenocarcinoma. The main goals are: (1) to enhance the efficacy of MBTA in the case of large tumors, (2) to enhance the efficacy of MBTA using a bilateral pancreatic adenocarcinoma mouse model, (3) to examine the potential of lipoteichoic acid to opsonize cancer cells and stimulate phagocytic cells.
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Study of Cancer Immunotherapy Mechanisms in Pancreatic Adenocarcinoma and Pheochromocytoma Murine Models
UHER, Ondřej
This dissertation examines the study of intratumoral cancer immunotherapy using a combination of phagocytosis-stimulating ligands and Toll-like receptor ligands (TLR) in murine pancreatic adenocarcinoma and pheochromocytoma murine models. In this study, we show that intratumoral application of the phagocytosis-stimulating ligand Mannan-BAM and three TLR ligands, referred to as MBT therapy, efficiently suppresses tumor growth in more than 83% of mice bearing murine melanoma. However, in aggressive pancreatic adenocarcinoma and pheochromocytoma murine models, such a combination is inefficient and must be combined with an agonistic anti-CD40 antibody, referred to as MBTA therapy, to achieve complete eradication of the tumor. We show that complex intratumoral MBTA therapy can systemically increase the recruitment of innate immune cells followed by activation of adaptive immune cells not only in treated tumors but also in distal non-treated lesions, resulting in the reduction of tumor growth and prolonged survival of treated mice. Taken together, these findings highlight the effect of MBTA therapy and the potential to optimize this therapeutic approach for future use in clinical trials as a treatment for metastatic cancers.
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Lineage plasticity of leukemic blasts. Importance for detection of minimal residual disease and study of hematopoesis
Vakrmanová, Barbora ; Mejstříková, Ester (advisor) ; Šálek, Cyril (referee) ; Klener, Pavel (referee)
Acute leukemia is the most common malignancy in children. According to the origin of the leukemic blasts, two types of leukemia are distinguished - lymphoid (ALL) and myeloid (AML). The focus of this thesis is lineage plasticity of the leukemic blasts. In about 2-5% of leukemias, blasts share immunophenotypic features of both lymphoid and myeloid lineages. In international retrospective study we showed superior overall survival in patients treated according to lymphoid type of protocol compared to patients treated to myeloid type of protocol, especially in cases with CD19 positivity on the blasts. Another type of the plasticity and diagnostic uncertainty in leukemia is ALL with early switch to monocytic lineage. About 8% of B cell precursor ALL underwent monocytic switch in our consecutive cohort. This phenomenon is more common among DUX4r, PAX5-P80R and ZNF384r leukemias. Discrepancy between minimal residual disease (MRD) measured by flow cytometry and quantitative assessment of immunoreceptor rearrangements method occurs because of the loss of B-lymphoid markers. We investigated transdifferentiation process by mass cytometry. By the multilabel panel we were able to determine the sequence of changes in proteins and transcription factors by new tviblindi algorithm. Targeted treatment, such as...
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Production of IL-2 fusion antibodies and determination of their biological activity
Frantová, Eliška ; Vaněk, Ondřej (advisor) ; Kubíčková, Božena (referee)
Interleukin 2 is a small cytokine with many important immune functions. It is used mainly as a T cell growth factor, but it also acts on other immune cells, especially NK and NK-T cells. IL- 2 at higher doses induces the differentiation and proliferation of the cell population of effector and memory T cells, which are characterized by cytotoxicity and are able to effectively defend the organism against pathogens and / or tumor cells. In contrast, low-dose IL-2 stimulates the Treg population, which suppresses immune responses and helps prevent autoimmune diseases. However, in cancer therapy, stimulation of this cell population is undesirable. Because free IL- 2 is toxic to the body at high doses, strategies have previously been proposed to potentiate the biological effect of IL-2. One of the most promising appears to be the single-stranded recombinant fusion construct, where IL-2 is covalently linked via an oligopeptide linker to an anti-IL-2 monoclonal antibody (mAb). Based on the findings of the studies of IL-2 / anti-IL-2 mAb immunocomplexes, this immunocytokine (IC) could provide significant therapeutic benefits in vivo, as compared to free IL-2, especially very robust strengthening of biological activity, selective stimulation of specific cell populations according to the selected antibody and...
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The importance of immunogenic cell death for modern tumor immunotherapy
Kubešová, Kateřina ; Šírová, Milada (advisor) ; Adkins, Irena (referee)
Immunogenic cell death is characterized by the release of molecules with damage-associated molecular patterns which can subsequently activate immune system. Only specific types of cell death can release these molecules. Classification of immunogenic cell death types and understanding of their initiation can be used for activation of the immune system against cancer cells. Simultaneously, it is necessary to understand different mechanisms, how the molecules with damage-associated molecular patterns work. Molecules with damage-associated molecular patterns which are studied the most, not only for their use in anticancer therapy, are type I interferons, calreticulin, high mobility group box 1 protein and heat shock proteins 70 and 90. Key words: immunogenic cell death, molecules with damage-associated molecular patterns, cancer, immunotherapy, type I interferons, calreticulin, high mobility group box 1 protein, ATP, heat shock protein 70, heat shock protein 90
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Influence of tumor microenvironment, cellular and humoral immunity on cancer pathogenesis.
Špaček, Jan ; Závadová, Eva (advisor) ; Petráková, Katarína (referee) ; Kopečková, Kateřina (referee)
Cancer is the second leading cause of death in the Czech Republic. Breast cancer and colorectal cancer have relatively high mortality rate. One of the areas of current clinical research in oncology is the study of prognostic biomarkers, which aims to optimize the decision-making process for a patient. Immune response and processes in the tumor microenvironment have been shown to influence to a large extent the biological nature of the tumor in terms of its aggressiveness and ability to metastasize in the host's body. There are certain tumors that could induce a strong immune response, while others do not. The ability to induce an anti-tumor cell response and to attract specific lymphocyte subpopulations directly into tumor tissue has been shown to be very closely related to the prognosis of cancer patients. There is evidence and correlation of the presence of so-called tumor infiltrating lymphocytes in tumor tissue and overall patient survival. Stratification of cancer patients based on immuno-predictors both in the plasma and directly in the tumor microenvironment makes it possible to identify suitable candidates for rediscovered modern anti-tumor immunotherapy, which can already be considered a standard therapeutic modality. In our projects, we focused on the identification of biomarkers that...
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Therapeutic use of alternative protein binders targeting tumor biomarkers in clinical testing of oncology patients
Tauš, Petr ; Drbal, Karel (advisor) ; Lepšík, Martin (referee)
Almost until the end of the last century, antibodies (aka immunoglobulins) were considered the only class of specific binding proteins. The discovery of hybridoma technology in 1975 had enabled the production of monoclonal antibodies and after twenty years some of them have entered clinical practice. Meanwhile, the first non-immunoglobulin protein scaffold, in which new specific binding sites could be introduced was discovered. To date, many different alternative scaffolds have been described, but only a few of them are being further developed for diagnostics, therapeutics or tools in basic research. Since these structures are overcoming the drawbacks of immunoglobulin structure, which are big size, expensive production and difficult rational design, they have potential to replace and exceed them. In this bachelor's thesis all the alternative scaffolds in development are summarized. Moreover, their advancements in clinical trials are described and compared with approved therapeutics based on immunoglobulin structure.
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Chimeric antigen receptors (CARs) in cancer treatment
Fejtková, Martina ; Macková, Jana (advisor) ; Fraiberk, Martin (referee)
Chimeric antigen receptor (CAR) is an artificial T-lymphocyte receptor consisting of extracellular single chain antibody serving as antigen binding site, transmembrane part and intracellular part which activates the cell. Therefore, it has the advantage of targeted specificity of monoclonal antibody and artificially strengthened activation of the T-lymphocyte by activation and costimulation domains. T-lymphocyte with CAR is able to locate and eliminate target cell with given surface antigen and also activate other compartments of the immune system by cytokine production. CAR T-lymphocytes have a huge potential for treatment of hematomalignancies and research also comes with new achievements in CAR modification for elimination of solid tumors.
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