The generally poor prognosis of patients with epithelial ovarian cancer patients treated with curative intent, calls for additional treatment modalities and possible success might lie in a... Show moreThe generally poor prognosis of patients with epithelial ovarian cancer patients treated with curative intent, calls for additional treatment modalities and possible success might lie in a combination of chemotherapy and immunotherapy. This thesis focuses on the interaction of chemotherapy with the immune system and describes new combined chemo-immunotherapy treatment strategies. This thesis has explored new strategies, immune-modulation of the IL-6 pathway and a vaccine against p53, to enhance immune surveillance and to disable tumour immune evasion in ovarian cancer patients. The future challenge for immunotherapy against ovarian cancer is a tailored combinatorial approach to test the rationale of potentially synergistic therapies that can induce efficient antitumour immunity and prolong patients’ survival. Show less
Trautinger, F.; Eder, J.; Assaf, C.; Bagot, M.; Cozzio, A.; Dummer, R.; ... ; Knobler, R. 2017
This thesis deals with aspects of diagnostics and immunotherapy of lung cancer. The first aim of this thesis is to investigate how the implementation of minimally invasive endoscopic ultrasound... Show moreThis thesis deals with aspects of diagnostics and immunotherapy of lung cancer. The first aim of this thesis is to investigate how the implementation of minimally invasive endoscopic ultrasound techniques (EUS and EBUS) in the staging algorithm of NSCLC can be optimized. The second aim of this thesis focuses on the role and potential of immunotherapy in lung cancer patients. Show less
Conventional therapies as chemotherapy and radiotherapy impact immune populations and immune responses in cervical cancer patients. This led to new perspectives into the important role of the... Show moreConventional therapies as chemotherapy and radiotherapy impact immune populations and immune responses in cervical cancer patients. This led to new perspectives into the important role of the immune system and possibilities to optimally implement immunotherapy in the treatment of cervical cancer. Immunotherapy with HPV16-SLP vaccination is a suitable candidate for combined therapy with chemotherapy, when administered within the optimal time window, as it maximizes vaccination efficacy while tumor-induces immune suppression is tackled. To eventually improve clinical outcome in cervical cancer patients, multimodality treatment approaches need further exploration. Within that approach, the assignment of treatment dose, timing and route of administration of both immunotherapy and the classic conventional therapies are important. In addition, individualization of patients therapy based on immune markers prior to treatment should be a goal to optimize combination therapy, minimize side effects and improve clinical outcomes. Show less
Ewing sarcoma is an aggressive primary malignant bone tumor with high degree of tumor vascularization and is the second most common sarcoma of bone in children and young adults. Patients... Show more Ewing sarcoma is an aggressive primary malignant bone tumor with high degree of tumor vascularization and is the second most common sarcoma of bone in children and young adults. Patients with disseminated disease at diagnosis or early relapse have a poor prognosis. To identify novel therapies and biomarkers for these patients we focused on the chemokines and chemokine receptors in Ewing sarcoma cells and their role its tumor microenvironment. CCL21 CXCL14, CXCR7 and the ratio between CXCR4-1 and CXCR4-2 have been identified as candidate prognostic markers, CCL21 immunotherapy as potential therapy and CXCR4 as potential therapeutic target in EWS. In addition, the presented peptide-based life cell imaging methods improve the ability to study CXCR4 cell membrane expression and dynamics qualitatively and quantitatively. This approach might be helpful for the measurement of anti-CXCR4 therapy efficacy. This work identified specific the chemokine signaling pathways that can be used to target Ewing sarcoma and its tumor microenvironment. Show less
Vulvar intraepithelial neoplasia is a chronic premalignant disease caused by a persistent human papillomavirus infection for which conventional surgical therapies are only partially successful with... Show moreVulvar intraepithelial neoplasia is a chronic premalignant disease caused by a persistent human papillomavirus infection for which conventional surgical therapies are only partially successful with high recurrence rates and psychosexual problems. Immunotherapy is a new form of therapy that stimulates the body__s own immune system to resolve infections and cancers. uVIN is the first HPV-induced disease successfully treated by immunotherapy, stressing the capacity of the immune system to deal with disease. Despite these considerable successes of immunotherapy, there is a need to identify parameters of the immune system which allow to select patients most likely to respond to treatment as well as to understand why others do not respond. The studies in this thesis resulted in the identification of a number of immuneparameters that positively or negatively predict the course of disease. These may be of great use as new prognostic biomarkers to identify patients most likely to respond to current successful immune therapeuties or identify patients at risk to the recurrent or progressive course of the disease. Moreover the knowledge of the immune profile may help to understand the non-responsiveness to immunotherapy of some patients. This can be used to optimize these therapies and to foster individualised (immune) therapies. Show less
Cervical cancer is caused by the human papillomavirus (HPV). The immune system plays an important role in the protection against HPV and failure of the immune system can lead to the development of... Show moreCervical cancer is caused by the human papillomavirus (HPV). The immune system plays an important role in the protection against HPV and failure of the immune system can lead to the development of cervical cancer. Immunotherapy aims at the restoration of an effective anti-tumour immunity. This thesis has led to new insights into the role of the immune system in HPV induced disease and forms a vital contribution to our understanding of tumor inducted immunesuppresion in patients with (pre-) cancerous lesions of the cervix. Furthermore it describes two clinical trails in which patients with pre-cancerous lesions of the cervix are vaccinated with an HPV16 E6/E7 synthetic overlapping long-peptide vaccine (HPV16-SLP). Multiple mechanisms restrain the host__s immune system to rise to the challenge of combating the tumour and favourable immune profiles need boosting in order to keep the balance in favour of tumour eradication. Future therapy should combine various synergistic approaches, and old and new therapies should be used side by side in order to enhance vaccination efficacy and counteract tumour suppression. Show less
Clostridium difficile is a spore-forming bacterium, the toxin-producing strains of which cause colitis. Risk factors are antibiotics, advanced age and severe comorbidity. C. difficile infection ... Show moreClostridium difficile is a spore-forming bacterium, the toxin-producing strains of which cause colitis. Risk factors are antibiotics, advanced age and severe comorbidity. C. difficile infection (CDI) has been regarded as mostly a hospital-acquired infection. Preventing relapses is considered the biggest challenge in CDI management. In this thesis, we show that CDI occurs in Dutch general practices, often in patients without contact with hospitals. Also, we show that the emerging virulent strain PCR ribotype 027 has not become dominant in European hospitals, but community-associated type 078 has become highly prevalent. Furthermore, we found that cystic fibrosis outpatients are frequently colonized with C. difficile, though mostly with nonpathogenic strains. Thus, acquisition of C. difficile in the community appears more important than previously thought. Next, we show that renal failure at the time of diagnosis predicts relapses. In addition, patients who fail to develop antibodies against C. difficile toxins have a higher chance of relapse. We describe an experimental product derived from the milk of cows vaccinated against C. difficile and its toxins, which might prevent relapses. The last part of the thesis consists of the European guideline for CDI treatment and its recent update Show less
Kelderman, S.; Heemskerk, B.; Tinteren, H. van; Brom, R.R.H. van den; Hospers, G.A.P.; Eertwegh, A.J.M. van den; ... ; Blank, C.U. 2014
High-grade osteosarcoma is a malignant bone tumor with the highest incidence in young patients. In chapter 2, we studied MSCs of osteosarcoma patients and found downregulation of HCLS1 in... Show moreHigh-grade osteosarcoma is a malignant bone tumor with the highest incidence in young patients. In chapter 2, we studied MSCs of osteosarcoma patients and found downregulation of HCLS1 in osteosarcoma patient derived MSCs as compared to healthy donor derived MSCs. Despite almost two years in culture, none of the samples underwent spontaneous transformation. An increase in binucleation was noted upon increasing passage in both osteosarcoma patient and healthy donor derived MSCs. In chapter 3, prognostic factors related to the survival of patients with pulmonary metastasized high-grade osteosarcoma were studied. Higher metastatic tumor burden (i.e. larger number of pulmonary nodules), presence of vital metastases upon resection and male sex were associated with an increased risk of death. In chapter 4 we show that osteosarcoma metastasis seems to be inhibited by the presence of macrophages in the tumor microenvironm ent. In chapters 5 and 6 we show that osteosarcoma cells are sensitive to lysis by both autologous and allogeneic NK cells. Patient derived NK cells can be adequately activated by cytokine treatment with IL-15 (chapter 5) or IFN-_ (chapter 6). Therefore, activation of autologous NK cells (either in vivo or ex vivo) may be efficacious. In conclusion, the activation of innate immune cells such as macrophages and NK cells is a promising new adjuvant treatment strategy to treat patients with high-grade osteosarcoma Show less
Osteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic... Show moreOsteosarcoma and Ewing sarcoma are the most common bone cancers in children and young adults. Despite advanced surgical techniques and multi-drug chemotherapy, patients with recurrent, metastatic or chemotherapy-resistant disease have a poor outcome. Thus, novel targeted therapies are needed that combine potent and specific anti-cancer activity with limited toxicity toward normal tissues. The thesis is introduced by an outline of the biological properties of osteosarcoma and Ewing sarcoma, followed by an overview of cancer immunology and immunotherapy with the primary focus on innate immunity of human natural killer (NK) cells and macrophages. In the research chapters, cellular interactions of NK cells and macrophages with bone tumor cells are characterized in order to achieve favorable effects on anti-cancer immune cell functions. It is demonstrated that the anti-cancer potential of especially NK cells but also macrophages can be enhanced and directed to the bone tumor cells. It is discussed that the modulation of tumor__immune cell interactions may help to design novel immunotherapeutic approaches to harness anti-cancer functions of innate immune cells against osteosarcoma and Ewing sarcoma. Show less
