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
T cell responses against tumor-antigens are frequently observed for some human malignancies, in particular melanoma. However, the spontaneous development of T cell responses of a sufficient... Show moreT cell responses against tumor-antigens are frequently observed for some human malignancies, in particular melanoma. However, the spontaneous development of T cell responses of a sufficient strength to eradicate human malignancies is rare. The transfer of T cell receptor (TCR) __ genes into autologous T cells, a process called TCR gene transfer, allows one to engineer antigen-specific T cell responses of interest. Over the last decade, TCR gene transfer has progressed to the stage of clinical evaluation as a strategy to engineer T cell responses against tumor-antigens, in order to treat metastatic melanoma and other malignancies. The scope of the work in this thesis is to advance the development of TCR gene transfer as an engineering strategy for T cell immunity against cancer. This involves the assessment of the safety of TCR gene transfer, the evaluation of strategies to enhance the function of TCR-modified T cells in vivo, and the development of technologies to identify tumor-reactive TCR__ genes Show less
Melanoma is a malignancy that arises from melanocytes, the pigment-producing cells that can be predominantly found in the eye or the epidermal basal layer of the skin. Mainly due to increased UV... Show moreMelanoma is a malignancy that arises from melanocytes, the pigment-producing cells that can be predominantly found in the eye or the epidermal basal layer of the skin. Mainly due to increased UV exposure, the incidence of melanoma has doubled worldwide over the past three decades (200.000 new cases in 2008). Primary melanomas can be easily treated by surgical resection, leading to a good prognosis for stage I patients. However, metastasized melanoma is almost completely resistant to therapeutic modalities such as radio- and chemotherapy, resulting in a median overall survival of less than one year for this patient group. Despite considerable efforts, for over 20 years there was no melanoma treatment developed that could improve survival of stage IV patients. However, the treatment of unresectable metastasized melanoma has progressed markedly in recent years due to the development of both immunotherapies that stimulate anti-tumor immunity and targeted therapies that block oncogenic proteins. This thesis will focus on pre-clinical work concerning the optimization of melanoma treatment. In detail, it will address for both targeted therapies and immunotherapies factors that play a role in the identification of response-predictive biomarkers, the toxicity of treatments, and the potential efficacy of combination treatments. Show less
Clinical studies demonstrated that HLA-DPB1 mismatched stem cell transplantation (SCT) is associated with a decreased risk of disease relapse and an increased risk of graft versus host disease ... Show moreClinical studies demonstrated that HLA-DPB1 mismatched stem cell transplantation (SCT) is associated with a decreased risk of disease relapse and an increased risk of graft versus host disease (GVHD) compared to HLA-DPB1 matched SCT. In T-cell depleted SCT, mismatching of HLA-DPB1 was not associated with an increased risk of severe GVHD, whereas a significant decreased risk of disease relapse was still observed. In this thesis we showed that HLA-DPB1 mismatched allo-SCT followed by donor lymphocyte infusion (DLI) late after transplantation can result in selective graft versus leukemia (GVL) reactivity. Although several studies have suggested that some HLA-DPB1-mismatches were less immunogenic, we demonstrated that all HLA-DPB1-mismatches as defined by allele typing are immunogenic and resulted in vitro in high frequency immune responses. Finally, in a cohort of 24 patients transplanted for various hematological ma lignancies with a 10 out 10 matched HLA-DPB1 mismatched SCT followed by DLI, HLA-DP specific immune responses were frequently found. The presence of HLA-DP specific CD4+ T cells correlated with clinical immune responses including both selective GVL-reactivity and GVHD. It is likely that in each individual local environmental circumstances possibly in combination with the induction of other immune responses may finally determine the balance between GVHD and GVL-reactivity HLA-DP HLA-class II mismatch alloreactivity hematopoietic stem cell transplantation donor lymphocyte infusion graft versus host disease graft versus leukemia reactivity immunotherapy Show less
Sonderen, A. van; Wirtz, P.W.; Verschuuren, J.J.G.M.; Titulaer, M.J. 2013
