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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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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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Regulační T lymfocyty a nádorová onemocnění
SKALIČKOVÁ, Markéta
The main aim of this thesis was to study the role of regulatory T cells in cancer. Their presence, importance, and mechanism of their action were studied as well. The practical part was focused on reduction of bigger tumors and suppressing regulatory T-cell effects. The combination of TLR agonists, agonistic CD40 antibody and anti-CTLA-4 was studied on a mouse model of pancreatic adenocarcinoma.
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