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Mannan-BAM, TLR ligands, and anti-CD40 immunotherapy in established murine pancreatic adenocarcinoma: understanding therapeutic potentials and limitations
VENHAUEROVÁ, Anna
The aim of this RNDr. Thesis is focused on understanding therapeutic potentials and limitations of the antitumor MBTA immunotherapy which is based on synergy of TLR agonists, anti-CD40, and phagocytosis stimulating ligands anchored into the tumor cell membranes. In this study, immunotherapy was tested in murine pancreatic adenocarcinoma Panc02 model. Firstly, the short-term and long-term efficacy of MBTA therapy was tested using established subcutaneous Panc02 tumors two times larger than in previous study. Secondly, the work is devoted to better understanding of the adaptive immunity involvement focusing on CD4+ and CD8+ T lymphocytes during the therapy and their effect on tumor volume reduction, long-term survival and resistance against tumor rechallenge. Subsequently, the ability of immunological memory to cross over the blood-brain barrier confirming its potential applicability in metastatic brain tumors was examined. Moreover, the antigen specificity of the immunological memory was evaluated. Finally, the potential of MBTA therapy to cure metastatic disease, represented by bilateral Panc02 mouse model, was studied. In this case, the MBTA therapy manifested a lower therapeutic response. Therefore, it was combined with diverse therapeutic approaches, such as intratumoral application of anti-CTLA-4 antibody, heat-killed Listeria monocytogenes, chemoablation using EtOH, targeting the tumor microenvironment by hyaluronidase, simultaneous injections of MBTA therapy in primary and secondary distant tumors, and its combination with RT. Despite all these combinations, our results showed that only simultaneous application of MBTA therapy into both tumors has potential for the treatment of the bilateral Panc02.
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The role of γc cytokines in the immune system and cancer immunotherapy
Ptáček, Bohumil ; Kovář, Marek (advisor) ; Adkins, Irena (referee)
Cytokines are proteins produced mostly by cells of hematopoietic origin and transduce signals via engaging cell surface receptors on either the cytokine-producing cells (autocrine signaling) or other target cells (paracrine signaling). Common cytokine receptor subunit (γc) cytokines are small glycoproteins belonging to type I cytokines with pleiotropic activities in both the innate and adaptive immune systems. All γc cytokines share a γc receptor subunit in their complete receptors. The first part of this thesis aims to summarize information about the biology of γc cytokines, their receptors, and their role in the immune system and its functions. The second part discusses the use of γc cytokines in cancer immunotherapy, presenting examples of particular γc cytokine therapies, and describes the approaches to improve the pharmacological features of γc cytokines or efficiently combine them with other immunotherapies and anticancer treatments. Keywords: γc cytokine, cytokine receptor, T cell, NK cell, cancer immunotherapy
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Studium imunitní paměti při imunoterapii pankreatického adenokarcinomu
DANIELOVÁ, Kristýna
This thesis is focused on immunotherapeutic strategy of pancreatic adenokarcinoma based on combination of TLR agonists, the ligands stimulating phagocytosis and monoclonal antibody anti-CD40. The aim of this thesis was to analyze the memory subpopulations of the T lymphocytes and efficacy of isolated CD3+ T lymphocytes from cured mice on pancreatic adenocarcinoma cell attachment.
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Imunoterapie pankreatického adenokarcinomu a jeho metastáz
FREJLACHOVÁ, Andrea
This thesis is focused on immunotherapy of pancreatic adenocarcinoma which is based on the synergy of TLR agonists with the ligands stimulating phagocytosis. The aim of this thesis was to analyze the infiltration of immune cells in untreated metastasis, to study the combination therapy of metastasis, and to look for ways to increase the effect of cancer immunotherapy. Panc02, the murine pancreatic adenocarcinoma model, was used for the experiments.
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Monitoring of immune parameters during anti-tumor immunotherapy
Bílková, Pavla ; Palich Fučíková, Jitka (advisor) ; Fialová, Anna (referee)
Dendritic cells are the most effective antigen presenting cells in humans, they stimulate naive T lymphocytes and thus initiate specific immune response. The discovery of dendritic cells and understanding of their functions contributed to the idea of usingdendritic cells for the treatment of cancer. Anti tumor immunotherapy is a therapeutic strategy that aims to induce and maintain immune responses against tumor cells. Currently, immunotherapy based on dendritic cells has strong position among other anti cancer therapies and seems to be a promising therapeutic option for patients with tumors. In this work, I evaluated the effectiveness of treatment in patients with prostate cancer treated with immunotherapy based on dendritic cells. I focused on the detection of antigen specific T lymphocytes in peripheral blood against tumor antigens, PSA, NY ESO 1, MAGE A1 and MAGE A3. Using a 3 day standard protocol for the detection of antigen specific T cells using intracellular cytokine staining we were able to detect only a small percentage of this minor population. Only after extension of the protocol, we increased the sensitivity setting and we detected a significantly increased frequency of antigen specific T lymphocytes in the peripheral blood after one year DC vaccines application.
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Expression of immunogenic cell death markers on lung cancer cells
Urbanová, Linda
Immunogenic cell death (ICD) is characterized by presence of specific molecules including surface exposed calreticulin (CRT) and the heat shock proteins HSP70 and HSP90. Release of ATP and high-mobility group box protein 1 (HMGB1) belongs to other typical characteristics. For induction of ICD in lung cancer cells high-hydrostatic pressure (HHP) was used. Treatment by HHP induces expression of immunogenic markers CRT, HSP70 and HSP90 on the cell surface. HHP also induces secretion of ATP to the extracellular milieu. Dendritic cells (DC) pulsed with HHP-treated tumor cells showed fenotypic maturation characterized by upregulation of maturation molecule CD83, costimulation molecules CD80 and CD86, chemokine receptor CCR7 and MHC class II molecule HLA-DR. Pulsed DCs have also higher rate of phagocytosis of HHP-treated tumor cells and they induce lower numbers of regulatory T cells compared to immature DCs. Moreover, activation of caspases (-8, -9, -3) and other proteins (phosphorylation of eIF2α) which are crucial in ER-stress mediated apoptotic pathway, was observed after HHP treatment. Using wide range of methods it was confirmed that HHP treatment is able to induce ICD in lung cancer cell lines, fenotypic and functional characteristics were described and the decreased induction of regulatory...
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Indoleamine 2,3-dioxygenase 1 inhibitors in cancer immunotherapy
Muffová, Barbora ; Poláková, Ingrid (advisor) ; Šroller, Vojtěch (referee)
The indoleamine 2,3-dioxygenase (IDO 1) enzyme is expressed in small amounts in most of the mammalian tissues, and its production is detected also in various types of tumours. IDO 1 catalyses the very first step of the kynurenine pathway, the tryptophan conversion to N-formylkynurenine, which is further metabolized to kynurenine (Kyn). The kynurenine/ tryptophan ratio (kyn/trp) may be used as a prognostic marker in research and treatment of IDO 1+ tumours. The kyn/trp demonstrates the activity of IDO 1 in tumours. The goal of cancer immunotherapy based on IDO 1 inhibition is to reverse or reduce the protumour effects of IDO 1, such as avoiding NK and T cells inhibition and activation of regulatory T cells or association with tumour-associated macrophages (TAM). IDO 1 inhibitors have been examined alone in monotherapy or together with cytotoxic T-lymphocytes antigen 4 (CTLA-4) inhibitors and programmed cell death protein 1 (PD-1) inhibitors in combined therapy. Recently, several studies are dedicated to invent inhibitors, which are able to inhibit the activity of other trp-catalysing enzymes, the indoleamine 2,3-dioxygenase 2 (IDO 2) and tryptophan 2,3-dioxygenase (TDO), together with the IDO 1 activity. Cancer immunotherapy based on IDO 1 inhibition may be combined also with chemotherapy.
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Oncolytic viruses in cancer immunotherapy
Zupko, Jakub ; Bartůňková, Jiřina (advisor) ; Janovec, Václav (referee)
Oncolytic virotherapy is a field dedicated to exploiting viruses in the battle against cancer, where their specific cytolytic effects are sorely needed. This work focuses on the mechanisms and limitations of oncolytic virotherapy, on the recent advances in the field and on the potential oncolytic viruses hold for the future.
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