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The clinical relevance of immunogenic cell death associated signalling and molecules in cancer therapy
Holíček, Peter ; Palich Fučíková, Jitka (advisor) ; Říhová, Blanka (referee) ; Starková, Júlia (referee)
The clinical relevance of immunogenic cell death-associated signaling and molecules in cancer therapy The capacity of cancer cells to induce anticancer immune responses relies on multiple factors, including the antigenic repertoire of cancer cells and their ability to provide adjuvant signals, as represented by danger-associated molecular patterns (DAMPs), which are exposed and released by malignant cells during immunogenic cell death (ICD). The release and secretion of DAMPs can orchestrate the activation of innate and adaptive tumor-targeting immunity, resulting in tumor regression. Various chemotherapies, radiation therapy, physical modalities, and targeted anticancer agents have been described as potent ICD inducers, which besides being directly cytotoxic, can activate clinically relevant anticancer immune responses. Therefore, patients whose tumor microenvironment (TME) is shows defective DAMP release or downstream DAMP-sensing signaling pathways do not fully benefit from ICD-inducing treatments, which can lead to overall therapeutic failure. My dissertation contributes to this field by exploring the impact of ICD on the development of innate anticancer immune responses, with a particular focus on natural killer (NK) cells, showing that surface-exposed calreticulin (ecto-CALR) positively impacts the...
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Immunomodulatory effect of tumor targeted polymer drugs
Mervartová, Ivana ; Šírová, Milada (advisor) ; Palich Fučíková, Jitka (referee)
5 Abstract Myeloid-derived suppressor cells (MDSC) are a very heterogeneous population of immature, activated myeloid progenitors of neutrophils, monocytes/macrophages and dendritic cells that have not differentiated into mature forms. A common feature of these cells is the ability to suppress immune responses of T cells, NK cells, and dendritic cells. It is known that MDSC accumulate under various pathological conditions, such as chronic inflammation or cancer. In breast cancer patients, the highest MDSC counts correlate with the occurrence of metastatic foci in lung tissue. The suppressive effects of MDSCs are associated with resistance to chemotherapy, reduced effectiveness of immunotherapy and overall poor prognosis of the disease. Therefore, many studies focus on MDSC. One possibility is the differentiation of MDSC into mature populations that lose their suppressive phenotype. In this work, we focused on modulation of MDSC activity by all-trans retinoic acid (ATRA), bound to a polymer conjugate based on N-(2-hydroxypropyl)methacrylamide (HPMA). ATRA is used in clinical practice for the treatment of acute promyelocytic leukemia, where the mechanism of action is the differentiation of pathological cells into more mature forms and thus the cessation of their proliferation. The binding of ATRA to the...
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Preparation of anti-cancer vaccine / / immunotherapy for ovarian cancer under conditions of good manufacturing practice
Fučíková, Jitka ; Jílek, Petr (advisor) ; Pávek, Petr (referee)
Generation of clinical-grade dendritic cell-based vaccine for immunotherapy of ovarian cancer Introduction: Dendritic cells (DCs) the most potent antigen presenting cells. Recent technological advances allow for generation of large numbers of DCs from peripheral blood monocytes. Administration of activated DCs loaded with tumor antigens is thus an attractive approach for immunotherapy of cancer. Prerequisite for the initiation of clinical trials in cancer immunotherapy is the development of protocols for DC-based vaccine generation according to Good Manufacturing Practice (GMP) conditions. Aim of the study: Development of protocol for the generation of clinical grade vaccine based on activated DCs loaded with killed tumor cells for use in the immunotherapy of ovarian cancer. Materials and methods: Immature DCs were generated from peripheral blood monocytes of healthy donors. We tested Cell Gro and RPMI+5% pooled human serum (5% PHS) as clinical grade culture media. Immature DCs were then activated by three distinct stimuli (Poly I:C, LPS and cocktail of proinflammatory cytokines (TNF, IL-1 and IL-6)). Activated DCs were evaluated for their phenotypic and functional characteristics and for their capacity to activate antigen specific and/or regulatory T cells. Results: Culture of monocytes in Cell Gro yielded...
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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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Identification of prognostic biomarkers for immunotherapy of ovarian carcinoma
Quaiserová, Lenka ; Palich Fučíková, Jitka (advisor) ; Říhová, Blanka (referee) ; Reiniš, Milan (referee)
Ovarian cancer belongs to the gynecological malignancies with the worst prognosis, mainly due to the late diagnosis of this disease and limited therapeutic options for patients. Despite the undeniable progress in surgical and chemotherapy treatment, the mortality of this disease is still rather high. For this reason, several preclinical and clinical studies have been involved in identification of new treatment strategies (including immunotherapy) and characterization of new prognostic and predictive biomarkers to help determine the development of the clinical condition of patients or their response to treatment. The aim of this thesis was to better understand the role of the immune system in the tumor microenvironment (TME) of high-grade serous ovarian cancer (HGSC) and its possible prognostic role in the treatment of patients. Our results show that the presence of activated DC-LAMP+ dendritic cells in the TME is associated with the induction of anti-tumor T helper type 1 response (Th1) and cytotoxic response. Surprisingly, the resulting effector activity of the cytotoxic T lymphocytes (CTLs) is not inhibited by the presence of programmed death-ligand 1 (PD-L1), programmed cell death (PD- 1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and lymphocyte-activation gene 3 (LAG-3), as...
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Overcoming cancer resistance to chemotherapy through HPMA copolymer conjugates
Sivák, Ladislav ; Kovář, Marek (advisor) ; Smetana, Karel (referee) ; Palich Fučíková, Jitka (referee)
Multidrug resistance (MDR) is a common cause of failure in chemotherapy for malignant diseases. Cancer cells develop MDR most often via the up-regulation of P- glycoprotein (P-gp) expression. P-gp is an efflux pump with broad specificity belonging to ATP-binding cassette (ABC) transporters which decreases the intracellular concentration of various drugs. We designed polymeric conjugates based on an N-(2-hydroxypropyl)methacrylamide (HPMA) bearing a cytostatic drug and/or P-gp inhibitor and tested their cytostatic/cytotoxic activity in vitro and their therapeutic efficacy in vivo in MDR tumors. We demonstrated that HPMA copolymer conjugates bearing both the cytostatic drug (doxorubicin (Dox) or pirarubicin) and the P-gp inhibitor (derivative of reversin 121 (R121) or ritonavir) possess remarkable cytostatic and cytotoxic activity in MDR tumor cell lines in vitro and superior antitumor activity in vivo. Notably, the HPMA copolymer conjugate bearing both Dox and R121 showed significant antitumor activity in both P388/MDR and CT26 mouse tumor models and was capable to completely cure 6 out of 8 mice with established CT26 tumors. We explored the potential of micelle-forming HPMA copolymer-poly(propylene oxide) (PPO) diblock bearing Dox to overcome MDR in vitro and in vivo. The HPMA copolymer-PPO diblock...
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Study of anti-tumor immune response in patients with lung cancer.
Myšíková, Dagmar ; Lischke, Robert (advisor) ; Bouček, Jan (referee) ; Palich Fučíková, Jitka (referee)
Lung cancer is the leading cause of cancer mortality worldwide. Understanding biological processes of specific antitumor immune response remains of an eminent interest and represents necessity for designing successful antitumor immunotherapeutic strategies. The theoretical part of the thesis describes components of the immune system that are involved in antitumor response and discusses their role in the hitherto known and used lung cancer immunotherapy. In the practical part of the thesis, two studies studying different aspects of anticancer immune response are described. Both studies were conducted in cooperation with 3rd Surgical Department 1st Faculty of Medicine, Charles University and University Hospital Motol and with the biotechnology company Sotio a.s. The first study is focused on the humoral component of the specific antitumor response and prospectively analyses serum frequency of antitumor antibodies against NY-ESO-1, Her2/neu and MAGE-A4 antigens in 121 patients with NSCLC. Here it was shown for the first time that tobacco smoking significantly increases the frequency of NY- ESO-1 antibodies in sera of smokers in comparison to ex-smokers and non-smokers. The second study is focused on the cellular component of the specific antitumor response investigating the activity of the dendritic...
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The prognostic and predictive role of immune check point inhibitors in ovarian cancer patients
Raková, Jana ; Palich Fučíková, Jitka (advisor) ; Šťastný, Marek (referee)
Epithelial ovarian cancer is the sixth most common tumor disease among women and it is the leading cause of death from all types of gynecologic malignancies. The current standart of care consist of debulking surgery followed by platinum-taxane chemotherapy. Althought some patients benefit from the treatment, most eventually experience platinum-resistance and die from this disease. Immunotherapy based on application of immune checkpoint blockers represents a new treatment strategy in different cancer malignancies. However, emerging clinical data show only limited clinical efficacy of these agents in ovarian cancer patients with objective response rates of 10-15%. Therefore there is a strong need to identify a potential biomarkers, which allows to identify the group of patients, who will benefit the most from this costly treatment. The aim of my diploma thesis was to characterize the prognostic and predictive role of the immune checkpoints within the retrospective and prospective cohort of patients with high-grade serous ovarian cancer (HGSOC). Our study follows, that the expression of PD-L1 molecule and high frequencies of PD-1+ tumor infiltrating lymphocytes (TILs) in tumor microenviroment is significantly correlated with a better prognosis of patients with HGSOC. Moreover, PD-L1 and PD-1...
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Biodegradable high molecular weight polymeric conjugates for efficient delivery of cytostatic drugs into solid tumors.
Černý, Viktor ; Kovář, Marek (advisor) ; Palich Fučíková, Jitka (referee)
Cancer remains one of the most pressing issues of contemporary science and medicine. Incidence of malignant diseases is rising worldwide and they represent a major problem for the society due to both economic and ethical issues they cause. Although the progress in cancer biology, therapy and immunology has led to the introduction of many novel therapeutic protocols, approaches and drugs with specificity defined on a molecular level into clinical practice, many malignancies retain their poor prognosis. Therefore, intense research into new ways to increase our therapeutic options is warranted. Unfortunately, bringing a completely novel drug into clinical use takes extremely high amounts of time and money and entails a high risk of failure. Therefore, a promising approach has been recently adopted which lies in repurposing compounds already used in human medicine for cancer treatment. This form of research can advance through clinical trials for a new indication much easier, faster and cheaper than researching completely new drugs. The aim of this study was to examine the anticancer potential of one such drug, mebendazole. An anthelminthic from the family of benzimidazoles, mebendazole has been in common clinical use from the 1970s and is marked by its low toxicity as well as its very low solubility....
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Evaluation of key parameters of the immune system in response to the treatment of active cellular immunotherapy DCVAC/PCa in patients with prostate cancer in II. phase of clinical trial.
Bílková, Pavla ; Palich Fučíková, Jitka (advisor) ; Froňková, Eva (referee)
Prostate cancer is one of the most common types of cancer in men, in developed countries. The treatment options for the advanced and relapsed stage of this disease are very limited. Immunotherapy seems to be a potential new alternative in the treatment of cancer. According to the theory of immune surveillance, the immune system recognizes and eliminates tumor cells by various of mechanisms in the early stages of the disease. Immunotherapy is a treatment method using both innate and adaptive immune mechanisms to activate anti-tumor immunity. Several clinical and preclinical studies of tumour immunotherapy illustrate several promising immunological principles to treat cancer. This is expecially relevant in the case of prostate cancer, as recent approval of sipuleucel-T by the US Food and Drug Administration marks the first antigen-specific immunotherapy approved for cancer treatment. Scientific team at department of Immunology, 2nd Medical school, hospital Motol and biotechnology company SOTIO is developing a next generation Active Cellular Immunotherapy based on activated dendritic cells, focusing on the treatment of prostate cancer. The aim of my thesis was to evaluate the presence of antigen specific immune response induced by immunotherapy by DCVAC/PCa in I./II. phase of clinical trial in two...
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