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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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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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Impact of pattern and functional properties of tumor-infiltrating immune cells for clinical outcome of head and neck cancer
Hladíková, Kamila ; Špíšek, Radek (advisor) ; Plzák, Jan (referee) ; Reiniš, Milan (referee)
Head and neck squamous cell carcinoma encompasses a complex and heterogeneous group of malignant diseases. Originally, this tumor type was associated with tobacco and alcohol consumption. However, a significantly expanding subset of tumors associated with oncogenic human papillomavirus infection arising in deep tonsillar crypts was identified within the last decades. Due to the essential role of the immune system in antiviral and anticancer immune response, the prognosis of patients is significantly influenced by the volume, composition and functional capacity of the immune infiltrate. The immunosuppressive landscape of head and neck cancer leads to unfavorable outcome of patients and decreased efficacy of immunotherapy. The response rate to standard treatment is high, however, standard therapy is accompanied by considerable toxicity influencing the quality of life. In 2016, the first immunotherapeutics for the treatment of patients with recurrent squamous cell carcinoma of the head and neck were approved - the anti-PD-1 immune checkpoint inhibitors nivolumab and pembrolizumab. This type of therapy, based on mitigation of immunosuppression, shows strong efficacy and less toxicity in combination with other therapies. Therefore, anti-PD-1 immunotherapy was recently approved in the first-line...
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Immune cells infiltrating premalignant lesions and invasive carcinomas associated with HPV infection
Dalewská, Natálie ; Tachezy, Ruth (advisor) ; Španielová, Hana (referee)
The immune system participates in many defence mechanisms of the body which in- volve the action of different types of immune cells. Immune cells play an important role in tumour development and progression. They infiltrate tumours and contribute to the tumour microenvironment. They are also implicated in diseases associated with human papillomavi- rus infection. Human papillomaviruses are viruses with oncogenic potential which cause in- fection in a number of anatomical locations of the human body. Such infection can lead to benign lesions, pre-invasive lesions, and invasive tumours. Pre-invasive lesions often re- gress spontaneously, but at advanced stages of the disease, progression to malignancy can occur. The tendency to regress or progress varies depending on the HPV genotype involved in the lesion and the quantity, type, and location of infiltrating immune cells. The synergy of these factors influences the prognosis and treatment of the disease, and, therefore, deter- mining the immunological score as an important diagnostic parameter becomes of utmost relevance. The knowledge of the effect of immune cells on tumour cells is useful in immunotherapy, which is based on the activation of the patient's own anti-tumour immune mechanisms. Immunotherapy is used in combination with systemic therapy...
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