Research Zwi Berneman

Abstract

Confidential .

Researcher(s)

• Promoter: Lion Eva
• Co-promoter: Anguille Sébastien
• Co-promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Based on the strong need for more targeted, tolerable and durable treatment strategies that could postpone or even prevent recurrence of disease in the most common adult malignant brain tumor, we embarked on a phase I/II clinical trial assessing frontline treatment with autologous dendritic cell (DC) vaccines loaded with glioblastoma-associated tumor antigen Wilms' tumor 1 in conjunction with conventional chemoradiation following surgery in adults with glioblastoma multiforme (GBM; NCT02649582). Childhood high-grade glioma (HGG, including GBM) and diffuse intrinsic pontine glioma (DIPG) are rare aggressive brain tumors. In the absence of a standard of care, treatment is mostly adapted from adult schedules, resulting in 5-year survival rates of less than 5% and 1% after diagnosis, respectively. With limited advanced investigational treatment options for this vulnerable patient population, we strive to extend our clinical study to the pediatric application. Ultimately working towards the clinical valorization of an adjuvant DC-based immunotherapy approach, health care evaluation is warranted. To this extent, we will include collection of patient-reported outcome on how the study therapy is experienced throughout time in the response evaluation of all study patients. As the search for biomarkers is gaining momentum in the rapidly evolving cancer immunotherapy landscape, we are also continuously expanding the screening assays on clinical patient material. The present project proposal is designed to allow completion of the intended adult GBM patient recruitment number and to extend the trial, innovating on the pediatric application of DC vaccination, health care evaluation and emerging therapeutic biomarker research. Within the context of hard-to-treat brain tumors, this study and its specific design will add a new dimension to our translational and clinical DC vaccine programs by investigating whether DC vaccination can be combined with first-line chemoradiation treatment of adult GBM and childhood HGG and DIPG patients and whether this combination leads to tumor-specific immune responses and improved survival. Exploration of patient-reported outcomes will help to improve symptom management, functional status and overall quality of life and will provide necessary information for future clinical valorization of this type of personalized medicine. In depth research on clinically valuable biomarkers will allow us to make a significant contribution to the broader (immunotherapy-oriented) scientific community.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: De Praeter Mania
• Co-promoter: Lion Eva
• Co-promoter: Norga Koenraad
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Improvement of first-line treatment for cancer patients with a high tumor recurrence rate and low effective treatment options, such as pancreatic cancer (PC), is warranted. Pancreatic cancer is a devastating disease with a 5-year survival rate below 5%, depending on the specific stage of disease when it is diagnosed, rendering it the 4th most common cause of cancer-related death worldwide. Even those who are eligible for curative-intent resection and conventional adjuvant treatment will nearly all die of their disease due to the high tendency towards recurrence. Adjuvant treatment with gemcitabine after resection of PC decreases recurrence rate, but the disease-free survival of these patients stays dismal with a 5-year survival rate below 21%, underscoring the need for new adjuvant regimens. The combination of gemcitabine with immunotherapy might improve outcome as suggested by some studies, but available data is so far limited to a few early-phase uncontrolled clinical trials. Interleukin (IL)-15-transpresenting dendritic cells (DCs) are a promising armament for immunotherapy of PC. Complementary to current treatments, DCs as quintessential antigen-presenting cells of the immune system can activate the antitumor immune system to attack pancreatic cancer cells. Preclinical data demonstrate the therapeutic potential of these innovative IL-15-transpresenting DCs evidenced by superior activation of the antitumor immune system to attack cancer cells. Since this will be the first-in-human use of IL-15-transpresenting DCs, the objectives are to test the safety, feasibility and immunopotency in patients with refractory solid tumors, the prototypic cancer patient population for phase I trials. This phase I clinical study is pivotal for future testing of this promising IL-15-transpresenting DC vaccine as adjuvant therapy to current anticancer regimens aiming to improve the standard of care of cancer patients with a high unmet medical need.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Lion Eva
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Cell therapy is an active area of immunological research and represents a highly innovative and rapidly expanding sector of pharmaceutical industry. The INsTRuCT Consortium answers an unmet need in the field for postdoctoral researchers experienced in scientifically excellent research and cell therapy development. INsTRuCT draws upon complementary expertise of its academic and industrial partners to offer a unique research and training programme. INsTRuCT proposes 15 distinctive research projects based at European companies or universities recognized for their scientific achievements and innovation. INsTRuCT is structured to promote interdisciplinary and intersectoral cooperation between partners, thereby accelerating pharmaceutical development and clinical application of novel myeloid regulatory cell (MRC)-based therapies. INsTRuCT is a primarily research-based training programme, which will be complemented by theoretical and practical training opportunities. INsTRuCT will encourage a translational view of research, which will be reinforced by intersectoral secondments. Teaching transferrable and communication skills is a high priority for INsTRuCT. ESR will gain a comprehensive overview of the drug development process in Europe as it applies to cell-based therapies; hence, INsTRuCT's graduates will be fitted for future roles as innovative leaders in the field. INsTRuCT will strengthen interactions between cooperating research groups at junior and senior levels, thereby promoting dissemination of standardized research approaches and data-sharing. Overall, INsTRuCT constitutes an original research and training concept that responds to the specific needs of a growing sector for postdoctoral scientists trained in Basic Immunology and cell therapy development. Consequently, INsTRuCT has a very high impact potential, both in terms of its scientific and technical advancements, and its future contribution to innovation and economic development within the European Union.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) and multiple myeloma (MM) are two types of blood cancers with a high unmet therapeutic need. The knowledge that cells of our immune system can recognize and kill cancer cells has laid the foundation for immune effector cell (IEC) therapy. This involves the infusion of immune cells that are "armored" outside the body with a T-cell receptor (TCR) or a chimeric antigen receptor (CAR). Such TCR- or CAR-loaded immune cells can execute a targeted attack against cancer cells. The aim of the present project is to improve the therapeutic efficacy of IEC therapy for AML and MM, while reducing the risk of side effects and costs of treatment. More specifically, immune cells will be weaponed with AML-directed TCRs or MM-directed CARs via a technique called electroporation. This involves the application of an electrical pulse to the cells, making temporary holes in their surface and enabling their loading with the TCR or CAR. When compared to the current IEC therapies, this novel procedure will allow for the generation of IECs with reduced costs, improved safety profile and enhanced anti-tumor activity. It is therefore expected that this research project will make an important contribution to the development of the next-generation IEC products for AML and MM.

Researcher(s)

• Promoter: Anguille Sébastien
• Promoter: Van Tendeloo Vigor
• Co-promoter: Berneman Zwi
• Fellow: Anguille Sébastien

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The extraordinary specificity of T lymphocytes for their antigen turns them into highly attractive and targeted immunotherapeutics. However, the scarcity of tumor-reactive T cells in cancer patients and the difficulty of their expansion in sufficient numbers for adoptive immunotherapy are substantial hurdles to broaden their clinical application. Transient introduction of a T cell receptor (TCR) specific for a pre-defined tumor-associated antigen by means of RNA-engineering into unselected bulk T cells would instantaneously confer redirected anti-tumor specificity to a large number of effector T cells for adoptive immune therapy with a built-in safety switch. This research project aims to investigate the generation, in vitro validation and preclinical testing of a set of Wilms' tumor 1 (WT1)-specific TCRs derived from leukemia patients that responded successfully to a therapeutic WT1 vaccine. On the short term, we are confident that this research project will provide a sound basis for exploratory and translational phase I trials using WT1-specific TCR mRNA-engineered T cells to study the safety (on- & off-target off-tumor effects) and feasibility of adoptive T cell therapy in patients with WT1-positive hematological malignancies. On the long term, adoptive T cell therapy using redirected T cells is poised to become a new treatment paradigm for both hematological and solid cancer patients at risk of relapse, if needed in combination with other antitumor therapies.

Researcher(s)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Anaphylaxis, potentially life-threatening, is one of the principal manifestations of systemic mastocytosis. In these patients anaphylaxis can result from IgEdependent and IgE-independent triggering of mast cells and/or basophils. However, the exact reasons for anaphylaxis in systemic mastocytosis remain a fundamental gap in our knowledge. This gap needs to be filled in order to optimize our patients' care and tailor their individual management. Indeed, the total mast cell burden, hitherto best reflected by the serum tryptase level, does not predict the risk of anaphylaxis nor its clinical outcome. Needless to stress that the uncertainties associated to their condition have a severe impact on the quality-of-life of the patient. Our hypothesis is that the occurrence of anaphylaxis in patients with systemic mastocytosis relates to an imbalance in activating and inhibitory pathways in mast cells and basophils, both critical effector cells of anaphylaxis. For this purpose we will first compare the immunophenotype of mast cells and basophils from patients with systemic mastocytosis with and without anaphylaxis. Secondly, we will study the behaviour of individual cells in response to various combinations of activators and inhibitors. As illustrated by our track-record we believe that this application fits into our overarching research. The Antwerp mastocytosis center will guarantee inclusion of the sufficient numbers of patients and healthy controls.

Researcher(s)

• Promoter: Ebo Didier
• Co-promoter: Berneman Zwi
• Fellow: Sabato Vito

Research team(s)

• Immunology

Project type(s)

• Research Project

Abstract

Development of three-dimensional (3D) in vitro cell culture models for human neuro-immunological research is currently a hot topic in medical cell biology research. Although multiple protocols have been described for generating human 3D brain organoids starting from pluripotent stem cells, current models display several limitations, including the lack of extracellular matrix (ECM), the absence of multiple types of immune cells and a functional blood-brain-barrier (BBB). With this project we aim to develop and optimize a new method for generating 3D neuro-immune cell culture models to study and modulate human neuro-inflammatory responses. For this, isogenic 3D cell cultures comprising human embryonic stem cell (hESC)-derived neurons, astrocytes and microglia will be established on decellularized mouse brain sections in order to provide growth and organizational support by original brain ECM proteins. In addition, hESC-derived astrocytes and endothelial cells will be used to create a BBB model for physical separation of hESC-derived macrophages. Further inclusion of genetic engineering strategies, to allow for real time bioluminescence imaging and (live cell) confocal microscopy, will be applied to ensure profound validation and high throughput screening applications. Once established, we will use this technology to further extend our research efforts to optimize therapeutic strategies based on interleukin (IL)13-mediated immunomodulation for cerebrovascular disease.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Berneman Zwi
• Fellow: Le Blon Debbie

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

We will study the contribution of hypoxia-inducible factors (HIF) to innate immunosuppression in glioblastoma (GBM) in hypoxia. The capacity of HIF inhibitors combined with the immunostimulant poly(I:C) to eliminate GBM cells will be studied in hypoxic cocultures of human GBM cells, natural killer cells and macrophages. This study will elucidate mechanisms of GBM-mediated immunosuppression and will generate valuable new insights for the development of novel efficacious immunotherapeutic strategies to treat GBM.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Fellow: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The five-year survival rate for acute myeloid leukemia (AML) is 26.6%, pointing to the need for new treatment options. We have recently provided the first clinical proof-of-concept evidence that vaccination with Wilms’ tumor 1 mRNA-electroporated dendritic cells (DC) can result in complete clearance of minimal residual disease. Our phase I/II study showed improved survival compared to historical data and demonstrable antileukemic effects. Now we want to confirm the results of our initial study in a multicenter randomized phase II clinical study in 138 patients with AML at high risk of relapse. The primary aim is to determine whether DC vaccination can significantly prevent relapse and increase survival. In addition, tumor marker levels and immune activation will be monitored. If the curative potential with low toxicity can be confirmed in this novel large randomized trial, our cell therapy can become a new standard postremission treatment for AML.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

The prognosis of patients diagnosed with malignant pleural mesothelioma (MPM) remains dismal with a median overall survival from diagnosis of only 12 months. The steadily increasing incidence of MPM along with the limited efficacy of the currently available treatment options for MPM prompts a search for new, more effective therapeutic modalities and strategies. Dendritic cells · (DCs), the immune system’s quinte-ssential antigen-presenting cells, are a promising armament for immunotherapy of MPM. In this phase 1/11 clinical study designed to improve most common care of MPM, DCs loaded with the mesothelioma-associated tumor antigen Wilms’ tumor 1 protein (WTl) will be used in conjunction with conventiona,l platinum/pemetrexed-based chemotherapy for the frontline treatment of newly diagnosed resectable and non-resectable MPM. Primary objective is to provide the first-in-human experimental demonstration that combining chemotherapy with WTl-targeted DC therapy is feasible and safe a·nd enables induction of systemic and in situ mesotheliomaspecific immune responses in MPM patients.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Dendritic cell (DC)-based cancer vaccines have been shown to be safe and well tolerated. Although there is a growing body of evidence that DC-based vaccination can be of clinical benefit, there is still room for improvement to enhance the potency and efficacy of the currently used DC vaccine preparations. In this context, new DC generation protocols that boost their immunogenic properties may provide an improved clinical benefit by a more powerful activation of T cells and natural killer (NK) cells, which could then optimally control or eliminate residual cancer cells. Therefore, a novel monocyte-derived DC generation protocol is being developed in vitro in this study focusing on two different strategies. First, conventional monocyte-derived IL 4 DC are being modified to express interleukin (IL )15 on their membrane by using IL-15 and IL 15Rα mRNA electroporation. I have shown that IL-15 can enhance the antitumor capacity of DC (Van den Bergh et al, J Cell Mol Med 2014) and that the IL-15/IL-15Rα-expressing designer DC have an improved capacity to activate NK cells (Van den Bergh et al, Oncotarget 2015). Now, I will investigate if this strategy also results in improved T cell activation. As a second innovation, the expression of programmed death ligands 1 and 2 (PD-L1 and PD-L2) will be inhibited, since both IL-15 and PD-L-silencing might be able to increase the antigen-specific T cell-stimulatory properties of the DC. To test this, the ability of the DC will be examined to induce or enhance the proliferation, degranulation, cytokine-producing capacity and cytotoxic profile of antigen-specific T cells. Overall, this study will generate valuable new insights into approaches to improve clinical outcome of DC-based cancer immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Berneman Zwi
• Fellow: Van den Bergh Johan

Research team(s)

Project type(s)

• Research Project

Abstract

To specifically advance translation initiatives of cell therapeutic advanced therapeutic medicinal products (ATMP) into commercially viable and safe treatments and hence, overcome regulatory, developer-related and value chain-related challenges, a consortium of stakeholders along the value chain, will, in collaboration with the sponsor, drive the ATMP through the early clinical trials with the objective to generate a lean manufactured and effective ATMP. The key concept is to task each of the specific necessary steps to the entity that is best suited for the task. It is important for all team members to understand, to some degree, the whole process involved in product development to adequately balance what needs to be done and more importantly when to do it as time and resources are not unlimited. Concrete tasks of this partnership are (i) upgrade the research 'product and process' to a lean manufacturing process with built-in quality measures, (ii) revise the whole process to generate an efficient, scalable process from patient to lab and back to patient, (iii) interact from an early stage with the Committee for Advanced Therapies (CAT) in the process of marketing authorization licensing and (iv) will support the sponsor in the licensing/spin-out of their ATMP project. In collaboration with an external consultant, different business models will be evaluated from which one concrete business case will be designed and serve as the basis to apply for further funding.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Berneman Zwi
• Co-promoter: Zakaria Nadia

Research team(s)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is an inflammatory disease that affects 1 out of 1000 people in Europe. MS is mediated by an autoimmune response to components or antigens of the insulating cover of the nerves of the central nervous system, i.e. myelin antigens, which are no longer recognised as being 'self'. This causes progressive destruction of the nerves of the brain and spinal cord, presenting as a wide range of motor and sensory disturbances. On the basis of our recent research, we hypothesise that specific cells of the immune system, i.e. dendritic cells (DC), regulate the immune response by inducing immunity or tolerance towards specific antigens. Therefore these DC might be used to suppress abnormal immune responses in autoimmune diseases such as MS. The final aim will be to induce tolerance to myelin antigens by administering DC to MS patients, which might lead to a change in the natural course of the disease. Several techniques exist for the loading of DC with specific antigens, which makes them tolerance inducing for specific autoimmune responses rather than being overall immunosuppressive. We will compare two of these techniques, in combination with a dose escalation vaccine study in MS patients in order to ensure patient safety when administrating a vaccine with tolerance-inducing DC. Patients will be divided in two groups, comparing both antigen-loading strategies by evaluating adverse events, relapse-free interval and immunological response after vaccination.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Cools Nathalie
• Co-promoter: Cras Patrick
• Fellow: Derdelinckx Judith

Research team(s)

Project type(s)

• Research Project

Abstract

Multiple sclerosis (MS) is the leading cause of non-traumatic disability in young adults. Although growing insights into disease mechanisms underlying MS have resulted in the development of new therapeutic strategies, none of the currently available treatments results in permanent stabilization or cure of MS. Current research efforts are focused on further unraveling MS immunopathogenesis as well as on finding ways to specifically manipulate disease-causing immune cells in order to treat MS. In this context, dendritic cells (DC) are set forth as interesting cellular targets. Post-mortem studies of MS brains as well as studies in animal models suggest that migration of DC from the bloodstream through the blood-brain barrier (BBB) and subsequent accumulation of these cells in the brain parenchyma represent crucial events in MS pathogenesis. Hence, DC and the process of DC migration are interesting targets for the development of new therapeutic strategies. Here, we will study the transmigratory capacity of circulating DC from MS patients using an in vitro BBB model. By studying differences in phenotype and function between migrating and non-migrating DC from MS patients and healthy controls, we aim to identify new therapeutic targets in order to interfere with DC recruitment to the brain. Ultimately, this will allow us to generate tolerogenic DC exhibiting enhanced migratory capacity, with the potential to suppress ongoing myelin-specific responses in the central nervous system.

Researcher(s)

• Promoter: Cools Nathalie
• Co-promoter: Berneman Zwi
• Fellow: Meena Megha

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

In this doctoral research proposal, we propose to combine both innate and adaptive immune stimulation approaches in order to mount a more potent anti-tumour response. In addition, an in-depth characterisation of central nervous system and peripheral immune changes will be performed following tumour induction and/or anti-tumour vaccination. With this research project we therefore aim to contribute to a better understanding of cellular interactions in the events of tumour growth and eradication, and to the improvement of current immunotherapeutic interventions of GBM.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Berneman Zwi
• Fellow: Hoornaert Chloé

Research team(s)

Project type(s)

• Research Project

Abstract

We will study the contribution of hypoxia-inducible factors (HIF) to innate immunosuppression in glioblastoma (GBM) in hypoxia. The capacity of HIF inhibitors combined with the immunostimulant poly(I:C) to eliminate GBM cells will be studied in hypoxic cocultures of human GBM cells, natural killer cells and macrophages. This study will elucidate mechanisms of GBM-mediated immunosuppression and will generate valuable new insights for the development of novel efficacious immunotherapeutic strategies to treat GBM.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Fellow: De Waele Jorrit

Research team(s)

Project type(s)

• Research Project

Abstract

Integrated vaccine and microbiological research with a focus on increasing the understanding of the immune response in prophylactic and therapeutic vaccines (including tumour vaccines) and on the containment of antibiotic resistance. Several innovative research topics are ongoing or in the pipeline: potential development of theranostic devices (e.g. rapid Point of Care Diagnostics, optical biosensors, lab-on-chip, microarrays) for pathogen detection and associated resistance in collaboration with several European research partners; potential development of new rapid diagnostic tests and injection devices; potential development of patient-specific cellular vaccines for targeted antiviral and anticancer therapy.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Berneman Zwi
• Co-promoter: Goossens Herman
• Co-promoter: Verwulgen Stijn
• Fellow: Bamberger Martina
• Fellow: Revets Hilde

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

This project represents a research contract awarded by the University of Antwerp. The supervisor provides the Antwerp University research mentioned in the title of the project under the conditions stipulated by the university.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Beutels Philippe
• Co-promoter: Leirs Herwig
• Co-promoter: Van Damme Pierre

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

In acute myeloid leukemia there is a strong need for new treatment strategies with low toxicity that can enhance survival by preventing relapse. We developed a safe and feasible Wilms' tumor 1 (WT1) mRNA-loaded autologous monocyte-derived dendritic cell (DC) vaccine capable of postponing or preventing relapse. Clinical responses were correlated with an increase in WT1-specific CD8+ Teelis and activated natural killer cells. Here, we aim to boost the therapeutic efficacy of DC vaccination. Two strategies with a recently proven capacity to enhance immune killer cell . activation in vitro will be compared in a phase 1/11 clinical study in AML, i.e. 1) . implementing the immunostimulatory molecules interleukin-15 and resiquimod in the DC generation protocol and 2) downregulating the inhibitory immune checkpoint proteins programmed-death ligand 1 and 2 on DC using silencing RNA. This study wil! generate valuable new insights into approaches to improve clinical outcome of DC-based immunotherapy.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

The main objective of the proposed project is to clinically evaluate autologous WT1-loaded DC vaccines that are generated using two novel protocols to optimize DC immunostimulatory capacities and to compare the results with those from our previous phase I/II and phase II clinical studies. The aim is to improve the capacity of WT1-loaded DC vaccines to prevent relapse by eliminating residual leukemic cells in AML patients in remission.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

In this doctoral research proposal, we propose to combine both innate and adaptive immune stimulation approaches in order to mount a more potent anti-tumour response. In addition, an in-depth characterisation of central nervous system and peripheral immune changes will be performed following tumour induction and/or anti-tumour vaccination. With this research project we therefore aim to contribute to a better understanding of cellular interactions in the events of tumour growth and eradication, and to the improvement of current immunotherapeutic interventions of GBM.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Berneman Zwi
• Fellow: Hoornaert Chloé

Research team(s)

Project type(s)

• Research Project

Abstract

With this phase I/II clinical study in newly diagnosed GBM patients, we want to evaluate our in-house developed immunotherapy with Wilms' tumor 1 (WT1) messenger ribonucleic acid (mRNA)-loaded autologous dendritic cells (DCs) in combination with adjuvant temozolomide chemotherapy, following maximal, safe surgical resection and temozolomide-based chemoradiation.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Specenier Pol

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other KBS. UA provides KBS research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Dendritic cells (DCs) are central mediators that keep the balance between immunity to foreign antigens and immune tolerance to self-proteins. Disruption of this balance may lead to disease. We aim to unravel the role of DCs in T-helper (Th)1/Th17-mediated immune diseases (including inflammatory bowel disease, multiple sclerosis, cardiovascular disease and rheumatoid arthritis), with the purpose to design novel DC-targeted therapeutic strategies.

Researcher(s)

• Promoter: Vrints Christiaan
• Co-promoter: Berneman Zwi
• Co-promoter: De Winter Benedicte
• Co-promoter: Ebo Didier
• Co-promoter: Schrijvers Dorien

Research team(s)

Project type(s)

• Research Project

Abstract

The steadily increasing incidence of malignant pleural mesothelioma (MPM) along with the limited efficacy of the currently available treatment options for MPM prompts a search for new, more effective therapeutic modalities and strategies. Dendritic cells (DCs), the immune system's quintessential antigen-presenting cells, are a promising armament for immunotherapy of MPM. In this ph ase 1/11 clinical study, DCs loaded with the mesotheliomaassociated tumor antigen Wilms' tumor 1 protein (WT1) will be used in conjunction with conventional chemotherapy for the frontline treatment of resectabie MPM. The primary objective of th is project is to provide the first-in-human experimental demonstration that the combination of chemotherapy with WT1-targeted DC therapy enables the induction of both systemic and in situ mesothelioma-specific immune responses in patients with MPM.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Germonpre Paul

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we want to further investigate and exploit the capacity of DC and Treg to correct or modulate pathogenic responses in MS patients. Current research will provide the foundation for the eventual development of a cellular vaccine for the treatment of MS. Depending on the results of this study it can be envisaged to treat patients suffering from MS with tolerogenic DC and/or immunosuppressive Treg in order to eliminate or inactivate autoreactive T cells.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Cools Nathalie

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand VLK. UA provides VLK research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we want to investigate the predictive value of WTt RNA levels in peripheral blood as a tumor marker for scoring effectiveness of WT1-targeted DC vaccination in AML patients and for predicting relapse. In addition to the tumor marker, we will also examine the tumor microenvironment by monitoring immune activation to judge response to the therapeutic cancer vaccine. In this way, we will be able to distinguish patients responding to the therapeutic DC vaccine from patients at high risk for relapse that need intensified follow-up and appropriate treatment at the moment of relapse.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Smits Evelien
• Co-promoter: Van Tendeloo Vigor
• Co-promoter: Vermeulen Katrien

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Lee Wai Ping

Research team(s)

Project type(s)

• Research Project

Abstract

In general, active antigen-specific cancer immunotherapy is aimed at generating a tumor antigen-targeted immune response that can eradicate (residual) malignant cells. This project is based on our large experience with DC vaccination with WT1 in AML patients. Our goal is to further increase the efficacy of antitumor immunotherapy by developing a multi-antigenic DC vaccine, capable of eliciting strong immunological responses with durable clinical results in patients with various hematological malignancies. Later, this approach could be extended to solid tumors.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Smits Evelien
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

For hematological malignancies, such as acute myeloid leukemia (AML), there is a strong need for novel, well-tolerated adjuvant treatments able to control or prevent the frequent relapse that is associated with these diseases. A promising strategy is autologous immunotherapy, which aims to stimulate the patient's own immune system to destroy residual malignant cells. With this project we want to investigate in vitro the feasibility and potency of a dendritic cell vaccine loaded with mRNA which codes for various tumor antigens.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Willemen Yannick

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research agreement between the UA and on the onther hand IWT. UA provides IWT research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Le Blon Debbie

Research team(s)

Project type(s)

• Research Project

Abstract

The project will evaluate the effect of mesenchymal stem cell therapy on myelodysplasia/acute myeloid leukemia, in the call "kom op tegen kanker".

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

This proposed multidisciplinary research consortium, consisting of 6 different laboratories from the University of Antwerp, aims to understand the cellular and/or functional interactions of NSC implants in healthy and injured neural tissue (cuprizone-mediated demyelinisation mouse model). With this research project, which focuses on the in vivo molecular and physiological control of NSC, we aim to contribute to the in vivo study and modulation of NSC migration, survival, differentiation and functional integration.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Giugliano Michele
• Co-promoter: Jorens Philippe
• Co-promoter: Pauwels Patrick
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Der Linden Annemie
• Co-promoter: Ysebaert Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

We first aim to identify and functionally describe immune-suppressive proteins and/or signalling molecules on glioma cells, which lead to inhibition of microglia. Then, we will develop strategies to modify microglia in order to prevent inhibition by glioma cells in vitro and in vivo. We specifically aim to genetically engineer microglia with 'short interfering RNAs' against receptors or signalling molecules involved in immune inhibition by GL261 cells in order to improve their cellular therapeutic potency.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Pauwels Patrick
• Co-promoter: Ponsaerts Peter
• Co-promoter: Ysebaert Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we aim to further elucidate the mechanisms leading to immune-mediated rejection of allografts in the CNS. For this, we will non-invasively (by in vivo bioluminescence imaging) identify the exact timing and degree of microglia immune-reactivity in relation to immune-mediated rejection of different allogeneic adult-, embryo- and placenta-derived cell populations.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Pauwels Patrick
• Co-promoter: Ponsaerts Peter
• Co-promoter: Van Der Linden Annemie
• Co-promoter: Ysebaert Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

The Wilms' tumor 1 (WTI) protein has been shown to be a universal tumor antigen overexpressed in many tumors, including malignant mesothelioma and breast carcinoma. In view of the T cell immunogenicity of WTI-derived peptides, immunostimulatory dendritic cells loaded with WT1 antigen hold promise as a universal, yet patient-specific, polyepitope cancer vaccine to treat residual disease. Here, autologous monocyte-derived dendritic cells will be transfected with mRNA coding for the entire WT1 antigen and injected intradermally as a cellular cancer vaccine in mesothelioma and breast cancer patients as adjuvant treatment after optimal debulking or after neo-adjuvant chemotherapy. In this project, we want to investigate the safety, feasibility and immunogenicity of such WTI-targeted cancer vaccine in an open-label phase I trial.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Germonpre Paul
• Co-promoter: Huizing Manon
• Co-promoter: Peeters Marc
• Co-promoter: Van de Velde Ann
• Co-promoter: Van Schil Paul
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

The purpose of the Chair is a full characferization of Von Willebrand Disease ( VWD) in Belgium, including all up-fo-date laboratory techniques, multimeric analysis and molecular investigation, and the setting up of a plasma and DNA bank for future research in VWD.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

This research project on immunotherapy aims to generate potent immunostimulatory human dendritic cells for the activation of tumor-specific cytotoxic T cell responses using acute myeloid leukemia (AML) as tumor model. This project comprises human in vitro research to determine how innate immune cells and -signals can be implemented in immunotherapy. In this way, the experiments will contribute to the improvement of immunotherapy, both for cancer and viral infectious diseases.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

The specific aim of this project is to outline and experimentally validate new approaches to leverage the immunotherapeutic potential of DCs in the setting of malignancy. Both direct and indirect strategies to enhance the immunostimulatory capacity of DCs will be investigated.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Anguille Sébastien

Research team(s)

Project type(s)

• Research Project

Abstract

We want to establish in this project the in vitro T-cell antigenicity of RHAMM when introduced into DC of patients with AML and MM. RHAMM will be introduced into the DC as messenger RNA by our in-house developed and widely recognized electroporation method ensuring effective antigen presentation to CD4+ and CD8+ Tcells.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Willemen Yannick

Research team(s)

Project type(s)

• Research Project

Abstract

This is a fundamental research project financed by the Research Foundation - Flanders (FWO). The project was subsidized after selection by the FWO-expert panel.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Integrated vaccine and microbiological research with a focus on increasing the understanding of the immune response in prophylactic and therapeutic vaccines (including tumour vaccines) and on the containment of antibiotic resistance. Several innovative research topics are ongoing or in the pipeline: potential development of theranostic devices (e.g. rapid Point of Care Diagnostics, optical biosensors, lab-on-chip, microarrays) for pathogen detection and associated resistance in collaboration with several European research partners; potential development of new rapid diagnostic tests and injection devices; potential development of patient-specific cellular vaccines for targeted antiviral and anticancer therapy.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Berneman Zwi
• Co-promoter: Goossens Herman
• Fellow: Janssens Anke
• Fellow: Vankerckhoven Vanessa

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

In this project, we want to further investigate and exploit the capacity of DC and Treg to correct or modulate pathogenic responses in MS patients. Current research will provide the foundation for the eventual development of a cellular vaccine for the treatment of MS. Depending on the results of this study it can be envisaged to treat patients suffering from MS with tolerogenic DC and/or immunosuppressive Treg in order to eliminate or inactivate autoreactive T cells.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Cools Nathalie

Research team(s)

Project type(s)

• Research Project

Abstract

Future research will be focussed on three main topics: 1) Characterization of neural stem cells. While culture conditions have recently been established for adherently growing NSC, many questions remain regarding: (a) optimal growth conditions, (b) identity, and (c) differentiation potential in vitro and in vivo. 2) In vivo migration and survival of neural stem cells. While NSC-based therapies have demonstrated beneficial outcome in animal models of neurotrauma and/or -inflammation, currently there is no detailed knowledge regarding in vivo survival, migration and function of transplanted NSC. 3) Immunobiology of neural stem cells. While NSC-based therapies are being developed worldwide in various animal models, currently there is no knowledge regarding the in vivo interaction between the brain's innate/adaptive immune system and allogeneic NSC implants.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Ponsaerts Peter

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a formal research agreement between UA and on the other hand VLK. UA provides VLK research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

Coordinated belgian representation of HIV research at international conferences and other fora is non-existant, in contrast to neighbouring countries, such as The Netherlands. To anticipate this, the Clinical AIDS Research (KAR) group, currently acting as consultation body for Flemish AIDS reference centers, will be transformedinto a belgian AIDS Research Consortium (BARC). By doing this, HIV research performed in Belgium by clinicians, immunologists, molecular and clinical virologists, epidemiologists and social scientists can be mapped in a more appropriate way. The BARC acts as a catalyst to bring information to the outside world and as an international contact point. In this way, a framework can be established with regard to the second objective, namely facilitating interactions between different research groups. As a third objective, scientific activities will be optimised at European level. In 2011, different HIV patient cohorts (eurosida, euroresist, ...) will be brought together in one big database: eurocoord. BARC will warrant the quality of entered data. In consulation with the different partners, usage of the information will be optimized, aiming further research of each partner in their specific area of experise.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we want to further investigate and exploit the capacity of DC and Treg to correct or modulate pathogenic responses in MS patients. Current research will provide the foundation for the eventual development of a cellular vaccine for the treatment of MS. Depending on the results of this study it can be envisaged to treat patients suffering from MS with tolerogenic DC and/or immunosuppressive Treg in order to eliminate or inactivate autoreactive T cells.

Researcher(s)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Berneman Zwi
• Co-promoter: Cools Nathalie
• Co-promoter: Cras Patrick
• Co-promoter: Ponsaerts Peter
• Co-promoter: Ysebaert Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

Despite recent progress in the treatment of acute myeloid leukemia (AML) and multiple myeloma (MM), a high percentage of patients with AML and MM relapse due to the persistence of residual malignant cells. Here, we propose to carry out active specific immunotherapy in AML patients in remission and MM patients by intradermal vaccination with autologous dendritic cells loaded with a triplet of mRNA coding for Wilm's tumor antigen (WT1), the receptor for hyaluronic acid-mediated motility (RHAMM) and IL-12p70. The main goals of this proposal is: 1) to test the feasibility and clinical safety of a polyvalent RNA-modified DC vaccine; 2) to investigate its capacity to induce anti-WT1/RHAMM T cell responses and 3) to assess any preliminary evidence of antileukemic or antimyeloma activity by objective response criteria in AML remission patients, as well as in the MM patients.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

In this project we will investigate the influence of acute myeloid leukemia cells loaded with Toll-like receptor (TLR) ligands on the activation of dendritic cells (DCs) and natural killer (NK) cells. The hypothesis is that leukemia cells loaded with TLR ligands are capable of activating the recently discovered helper function of NK cells, so these NK cells can effectuate the polarization of immature DCs to T helper type 1 (Th1)-polarised DCs (DC1NK). This cross-talk between the innate and adaptive immune system in which DC1NK play a central role, would then facilitate the activation of antigen-specific Th1 cells and cytotoxic T lymphocytes.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Lion Eva

Research team(s)

Project type(s)

• Research Project

Abstract

Current project concerns a new generation, user-friendly, high-speed and compact flow cytometric cell sorter, capable of sorting different cell populations simultaneously, based on their intrinsic characteristics. This warrants further biological, molecular-biological and immunological research of sorted and purified cells.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Ebo Didier
• Co-promoter: Stevens Wim
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

The subject of this PhD project has to be situated within the framework of existing research activities at the Laboratory of Experimental Haematology focusing on the effects of innate immune signals on leukaemic tumor cells. This project aims to augment the immunogenicity of leukaemic cells through Toll-like receptor stimulation in order to (1) modulate the maturation stage of dendritic cells and to (2) subsequently potentiate a powerful acute myeloid leukemia-specific T-cell response.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Anguille Sébastien

Research team(s)

Project type(s)

• Research Project

Abstract

The prevention and treatment of bacterial and viral infections are the main focus of the Methusalem project VAXINFECTIO. Antibiotic resistance, anti-tumoral and antiviral cellular immune responses by dendritic cells, the evaluation of vaccination, and the socio-economic aspects of the use of vaccines and antibiotics are research topics that will be addressed. The Vaccine & Infectious Disease Instituut (VAXINFECTIO) of the Universiteit Antwerpen - consisting of the Laboratory of Medical Microbiology (LMM), the Laboratory of Experimental Hematology (LEH) and the Centre for the Evaluation of Vaccination (CEV) - maintains a close collaboration with the Centre for Statistics (CenStat) of the Universiteit Hasselt.

Researcher(s)

• Promoter: Goossens Herman
• Co-promoter: Berneman Zwi
• Co-promoter: Van Damme Pierre

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

With the aging of the population, degenerative and ischemic disorders are becoming an increasing economic and social burden. The characterization over the last decade of tissue specific stem cells other than hematopoietic stem cells (HSCs) including neural stem cells, mesenchymal stem cells and others, as well as pluripotent stem cells such as embryonic stem cells (ESCs) or multipotent adult progenitor cells (MAPCs) offers the possibility that stem cells may be used to treat disorders caused by degeneration or ischemia. The major advantage of HSC therapy is that the fate of the cells and their progeny can be readily followed by simple analysis of circulating blood or bone marrow biopsies. By contrast, the fate of stem cells resident in or grafted in solid organs can not be readily followed. Hence one of the major impediments to determine if stem cells might be exploited to treat disorders of solid organs is the inability to follow the fate (such as migration, survival and lineage differentiation) of stem cells, whether endogenous to the affected organ or grafted in the organ, in vivo using non-invasive means. Therefore, we have assembled a group of investigators from the K.U.LEUVEN, UNIVERSITEIT ANTWERPEN and UNIVERSITEIT GENT, who are recognized worldwide for their expertise in respectively stem cell research, non-invasive imaging technology and micro-& nanomaterials for biomedical and pharmaceutical purposes .. The consortium will develop methods to manipulate endogenous stem cells as well as cultured multipotent stem cell populations that can be grafted to enable non-invasive imaging of migration and survival of the cells in vivo, and to also enhance migration and survival. In a second platform multimodality imaging will be developed to allow in a non-invasive manner to follow the fate of stem cells in vivo. Some of these imaging modalities, here focused around stem cells, should be readily translatable to the clinic both to follow stem cell fate, but also outside of the area of stem cell research as we believe that some of the technical optimization of CT-scan, PET-scan and MRI based non-invasive imaging should have much broader applications. Moreover, development of genetic and direct labeling methods of stem cells to allow following their fate as well as modify their fate should prove very useful for studies aimed at testing the effect of drugs on stem cell or more differentiated cell behavior in vivo. Thus: although stroke will be used as the model disease, and MSCs, MAPCs and endogenous NSCs are the cells to be modified, this technology will constitute a generic but innovative set of methods that can then be used in other disease models, employing other stem cell populations, and outside the field of stem cell based and derived therapies.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

In secondary controllers, HAART and the immune system have induced viral mutations in Gag, Pol and Env, which have resulted in lowered viral fitness and immune protection. Some mutations have generated neoepitopes, which have induced cross-reacting and polyfunctional T cell responses against Gag-Pol and broad cross-neutralizing antibodies against Env. This type of immune responses and the associated normalizations of pathological hyper-activation constitute useful correlates of protection. The neo-epitopes could be included in immunotherapy as well.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

In this project, we will investigate the cellular and molecular determinants for optimal activation of human Th 1-polarized DC (DC 1 NK) in a AML tumor model. Our strategy will be to increase the immunogenicity of leukemia cells by loading them with TLR ligands whether or not in combination with transient transfection of immune-stimulating factors in order to trigger DC and NK activation for subsequent cross-priming of Thl/CTL cells.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the project is to develop a translational platform for integrated vaccine research, building upon the expertise of the Vaccine and Infectious Diseases Institute as regards the set-up and implementation of vaccine trials (phase I-IV), microbiological diagnostics and basic immunological research. This platform will operate according to ISO standards, and thanks to a swift transition from lab to 'bed-side', and to a swift feedback from bed-side to lab, will guarantee a fast development of a new generation of HPV vaccines. This platform will create the opportunity, in collaboration with the industrial partner, to develop serological and urine tests for early efficacy testing and follow-up of vaccinees. In addition, basic research into the mucosal cellular immunity can be initiated within this cooperation structure. The financial input of this project will allow the Institute to consolidate the available knowledge of HPV-testing and to further develop this knowledge with a clear focus on economic valorisation; furthermore, the existing collaboration with the pharmaceutical industry will get an additional dimension with new opportunities of expansion and collaboration.

Researcher(s)

• Promoter: Van Damme Pierre
• Co-promoter: Berneman Zwi
• Co-promoter: Goossens Herman

Research team(s)

Project type(s)

• Research Project

Abstract

The goal of this project is to analyze the conditions of access, quality and safety of stem cell research, from the perspective of ethical-legal principles of the autonomy of the person and the protection of the embryo, in interaction with the constant evolution of medicine.

Researcher(s)

• Promoter: Vansweevelt Thierry
• Co-promoter: Berneman Zwi

Research team(s)

• Personal Rights and Property Rights

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Reekmans Kristien

Research team(s)

Project type(s)

• Research Project

Abstract

In this EU project, partners UA (Antwerp) and KUL (Leuven) will investigate whether transient genetic modification of cord blood and bone marrow hematopoïetic stem cells with mRNAs encoding transcription factors, growth factors and receptors (all involved in self-renewal and migration of stem cells) results in improved in vivo repopulation of SCID mice. This research will lead to improved methodology for hematopoietic stem cell transplantation in adults and children.

Researcher(s)

• Promoter: Ponsaerts Peter
• Co-promoter: Berneman Zwi
• Co-promoter: Van Bockstaele Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

Developing new therapeutic strategies against HIV is a high priority: 80% of patients have developed resistance to some of the current drugs and transmission of drug-resistant virus is becoming a threat. While not aiming to evaluate new therapies in the clinic, this project will provide the basic research needed for the development of the following new treatment strategies.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Vanham Guido
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

This project will investigate whether transplantation of defined embryonic stem cell-derived neural stem cells (ES-NSC), genetically modified to secrete neurotrophic factors, can support or improve recovery after TBI and SCI. An improved recovery can be due to: A) a decreased secondary neural loss due to secretion of neurotrophic factors, and/or B) an enhanced neural recovery due to functional integration of transplanted ES-NSC and/or recruited endogenous NSC.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: De Deyn Peter
• Co-promoter: Jorens Philippe
• Co-promoter: Van Bockstaele Dirk
• Co-promoter: Van Marck Eric
• Co-promoter: Ysebaert Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

High-dose chemotherapy followed by allogeneic bone marrow or stem cell transplantation (alloSCT) is often used to treat acute leukemia patients. After transplantation, immunodeficiency persists for a prolonged period, especially in recipients who receive additional immunosuppressive drugs to prevent graft-versus-host disease. Reactivation of human cytomegalovirus (CMV) is frequently seen in aIlo-SCT patients and is a major cause of treatment-related mortality. Here, we describe a phase 1 dose escalation trial using CMV pp65- modified autologous dendritic cells in allo-SCT recipients. The primary objective will be to study the safety and feasibility of this treatment in a first set of patients. The secondary objective is to investigate restoration of CMV immunity post-allo-SCT in a larger set of vaccinated patients.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The primary objective os this phase I/II pilot study is to determine the safety and toxicity of the subcutaneous and intradermal (sc/id) administration of autologous DC electroporated with mRNA encoding Tat, Rev, Nef and Gag in HIV-1 infected patients who are virologically and immunologically responding to HAART.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

In this project we will investigate the influence of acute myeloid leukemia cells loaded with Toll-like receptor (TLR) ligands on the activation of dendritic cells (DCs) and natural killer (NK) cells. The hypothesis is that leukemia cells loaded with TLR ligands are capable of activating the recently discovered helper function of NK cells, so these NK cells can effectuate the polarization of immature DCs to T helper type 1 (Th1)-polarised DCs (DC1NK). This cross-talk between the innate and adaptive immune system in which DC1NK play a central role, would then facilitate the activation of antigen-specific Th1 cells and cytotoxic T lymphocytes.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Lion Eva

Research team(s)

Project type(s)

• Research Project

Abstract

This project will investigate whether transplantation of defined embryonic stem cell-derived neural stem cells (ES-NSC), genetically modified to secrete neurotrophic factors, can support or improve recovery after TBI and SCI. An improved recovery can be due to: A) a decreased secondary neural loss due to secretion of neurotrophic factors, and/or B) an enhanced neural recovery due to functional integration of transplanted ES-NSC and/or recruited endogenous NSC.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Ponsaerts Peter

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Stevens Wim
• Co-promoter: Berneman Zwi
• Co-promoter: De Clerck Luc
• Co-promoter: Ebo Didier
• Co-promoter: Hagendorens Margo
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi
• Promoter: Van Damme Pierre
• Co-promoter: Van Bockstaele Dirk
• Co-promoter: Van Tendeloo Vigor

Research team(s)

• Centre for the Evaluation of Vaccination (CEV)

Project type(s)

• Research Project

Abstract

The power of the human immune system can be applied for the development of more specific immunotherapy for cancer and HIV infection. We will investigate the immunostimulatory potential of human dendritic cells (DC) loaded with tumor or HIV antigens in vitro. Knowledge regarding the DC-induced immune response can be used for the development of more effective therapeutic vaccines for cancer and HIV.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Vanham Guido
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

This project concerns a phase Ib dose escalation trial of mRNA-transfected autologous dendritic cell vaccination. Patients with acute myeloid leukemia (AML) in remission and eligible for the study endpoints will be enrolled in order to study the anti-leukemic immune response and to prevent disease relapse. The first dose level as well as the next two levels are fixed in advance. The size of cohorts of patients will be 3 patients for each dose level. The primary objective is to investigate the feasibility and toxicity of dendritic cell therapy targeting the Wilms' tumor protein WT1 in patients with AML in remission. The secondary objectives are to investigate whether there is induction of WT1-specific antileukemic immune response and to describe molecular remission based on WT1 expression in the bone marrow and/or peripheral blood. Lastly, we will monitor overall and recurrence-free survival in the vaccinated patients.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) as a potential cancer vaccine. Human dendritic cells (DC) from healthy individuals, treated cancer patients and HIV positive individuals will be cultured starting from peripheral blood monocytes. The major aim is to transfer defined tumor and HIV antigens to DC by means of transfection of DC with mRNA encoding defined antigens. Antigen-loaded DC will be used for induction of antigen-specific autologous cytotoxic T cells capable of eradicating autologous tumor cells or HIV-infected cells. In a later phase, DC will be loaded with unfractionated tumor antigens (total tumor mRNA, apoptotic tumor cells). This approach will be tested using tumor material derived from cervix cancer and lymphoma patients.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

The Wilms' tumor (WT1 ) protein is highly overexpressed in a number of human cancers including hematological malignancies, lung, thyroid, breast, testicular, skin and ovarian carcinomas. Therefore, WT1 represents a potential universal tumor antigen which could be very useful for the design of therapeutic cancer vaccines. By using in vitro cultured myeloid dendritic cells transfected by mRNA electroporation with the WT1 gene, we want to explore the feasibility to stimulate in vitro WT1-specific cytotoxic T lymphocytes from cancer patients, that can specifically lyse autologous WT1 + tumor cells. This research could set the stage for development of a WT1-based dendritic cell vaccine for multiple cancer types.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

Despite new surgical techniques, pharmacological treatments and functional neurological stimulation methods, brain and spinal cord injuries remain a large medical and social problem. Therefore novel research aims at the development of new therapies reaching further than current revalidation strategies. Stem cell research offers promising opportunities for the development of new methods in order to repair or replace damaged tissues or cells. Stem cells have the potential to differentiate towards a neural phenotype, creating the possibility to replace cerebral or spinal neurons, astrocytes and oligodendrocytes. The goal of this project is to investigate whether embryonic stem cells, both mouse and human, genetically loaded with mRNA encoding neural key regulatory genes can differentiate towards neural cell types in vitro and in vivo (mouse model).

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Ponsaerts Peter
• Fellow: Van den Eeden Leen

Research team(s)

Project type(s)

• Research Project

Abstract

The Wilms' tumor (WT1) protein is highly overexpressed in a number of human cancers including hematological malignancies, lung, breast, testicular, skin and ovarian carcinomas. Therefore, WT1 represents a potential universal tumor antigen that could be very useful for the design of therapeutic cancer vaccines. By using in vitro cultured myeloid dendritic cells transfected by mRNA electroporation with the WT1 gene, we want to explore the feasibility to stimulate in vitro WT1-specific cytotoxic T lymphocytes from cancer patients, that can specifically kill autologous WT1+ tumor cells. This research could set the stage for development of a WT1-based dendritic cell vaccine for multiple cancer types.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the project is to induce a strong HIV-specific T-cell response, through loading of antigen-presenting cells (APC), more specific dendritic cells (DC) with Tat and/or Rev antigens, possibly in combination with Gag messenger RNA (mRNA). The ex vivo loading of autologous DC with Tat and/or Rev allows us to optimize the antigen dose, the DC type and the antigen loading method. Moreover, this method permits us to study the role of HIV-specific CD4+ Th1 cells at the induction and sustaining of a HIV-specific CTL effector response in vitro, at which CTL-mediated lysis of infected cells and eradication of the virus can be set as an endpoint.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Den Bosch Glenn A L

Research team(s)

Project type(s)

• Research Project

Abstract

Cervical cancer is the third most common cancer among women worldwide. Despite the progress in current therapies, these common treatments still have several disadvantages. On the one side is it impossible to remove all occurred micrometastases with surgery. On the other hand do radio- and chemotherapy not exclusively attack tumour tissue, but also exert a toxic effect on normal tissues and suppress the immune system. Therefore current research aims novel and more effective therapies. Loading dendritic cells with tumour antigens for the induction of anti-tumour immunity is at this moment a 'hot topic' of experimental immunotherapy. The principle of immunotherapy is to specifically stimulate the immune system for generating a tumour specific immune response. Cervical cancer is linked with human papilloma virus (HPV) infection. Although there are over 20 oncogenic HPV genotypes, HPV type 16 and 18 are the most prevalent in cervix carcinoma. The principle of a therapeutic vaccine consists in presenting HPV related antigens, such as E6 and E7 viral proteins, to professional antigen presenting cells (APC), especially dendritic cells (DC), to induce a strong T-cell response. The shape, in which the HPV antigens are presented to the DC, determines for a great part the type and the strength of the resulting T-cell response. The current challenge is determining the most efficient way in using modified DC in immunotherapeutic protocols . The generation of an optimal cellular anti-tumour response implies the activation of tumour specific CD8+ cytotoxic T-cells. However, more and more studies underline the important role of CD4+ T-cells in the regulation of the immune response. We aim in this project at the generation of a strong HPV specific CD4-positive as well as a CD8-positive immune response. For this purpose, we will generate cDNA constructs for the in vitro transcription of HPV 16 E6 and E7 mRNA, if necessary in combination with MHC class II signalling sequences (e.g. LAMP-I). The functionality of the produced mRNA shall be tested after transfection of DC with this mRNA. We will demonstrate protein expression with Western Blotting, while MHC class I and/or class II presentation of the antigenic peptides shall be tested with peptide-specific CD8+ or CD4+ T-cell clones. We shall also start with the development of an in vitro T-cell activation protocol for the generation of HPV 16 E6 and E7 specific T-cells with peptide pulsed DC. Furthermore, we shall start up an ex vivo study, more specific in the second term of the project, on the basis of the developed strategy during the first term. We will determine whether in vitro an autologous immune response can be elucidated against the tumour cells of a patient. For this purpose, we shall generate DC from peripheral blood samples of cervix carcinoma patients and modify these DC with mRNA coding for HPV antigens. After in vitro activation of autologous T-cells, we shall determine if there is sufficient reactivity against autologous tumour cells of the patients. The ultimate goal of these experiments is the development of an efficient strategy that can be used in a clinical model.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Cools Nathalie

Research team(s)

Project type(s)

• Research Project

Abstract

Cells, electroporated with messenger RNA, are able to present antigenic epitopes in association with class I MHC molecules to activate a CD8+ T cell immune response. The aim of the following study is to find out if messenger RNA electroporated dendritic cells can be used for the in vitro induction of different T cell subsets. These subsets include CD4+ helper T cells type 1, CD8+ cytotoxic T cells type 1, regulatory T cells, CD4+ helper T cells type 2 and CD8+ cytotoxic T cells type 2.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Jorens Philippe
• Co-promoter: Berneman Zwi
• Co-promoter: Buytaert Philippe
• Co-promoter: Cras Patrick
• Co-promoter: Delbeke Luc
• Co-promoter: Van Bockstaele Dirk
• Co-promoter: Van Bogaert Pierre-Paul
• Co-promoter: Van Tendeloo Vigor
• Co-promoter: Verlooy Jan

Research team(s)

• Laboratory Experimental Medicine and Pediatrics (LEMP)

Project type(s)

• Research Project

Abstract

It has been shown that HIV-1 seropositive patients without disease progression exhibit a strong HIV-specific CD4+ and CD8+ T-cell immunity. Moreover, even HIV-specific CD8+ cytototoxic T-lymphocytes (CTL) can be observed in HIV-1 patients with a progressive disease course. These cells however appear to be functionally deficient. This suggests that the qualitative enhancement and boosting of T cell responses against HIV may have a beneficial influence on the disease progression. Treatment with `highly active anti-retroviral therapy' (HAART) drugs suppresses the viral replication, but is not able to eradicate the virus completely. Furthermore, HAART diminishes the anti-HIV CTL response and does not lead to a complete reconstitution of the HIV-specific CD4+ T-helper cells. Eliciting a strong cellular immune response against the regulatory HIV proteins Tat and Rev may be of great importance in the elimination of the virus. Hence, the main goal of this project is the ex vivo sensitisation of T cells of HAART patients by loading of autologous monocyte-derived dendritic cells (Mo-DCs) with mRNA coding for the regulatory HIV proteins Tat and Rev (alone or in combination with the structural HIV protein Gag). We will not only focus on the induction of CD8+ HIV-specific CTLs, but also on the specific conditioning of DCs for the activation CD4+ T helper cells, which can enhance the anti-HIV CTL response. Our laboratories are experienced in the in vitro culturing of DCs, and also in the electroporation transfection technique which will be used for loading of the obtained dendritic cells with HIV-1 mRNA. So, in this project we would like to demonstrate that eliciting and/boosting of the cellular immune response against the early HIV antigens Tat and Rev plays a key role in the development of a HIV immunotherapy.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Colebunders Robert
• Co-promoter: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

About 25 % of the European population develops a form of allergy during his life. In the daily life, everyone is exposed to all sorts of products that can lead to an allergic reaction, for example make-up, soap, salve, medication, perfume,' The skin is usually the main target. Companies like l'Oréal, that produce make-up and salves, and also the pharmaceutical industry, have to test the allergic potential of their product. Most approaches to this form of predictive testing are based upon the use of animals or human volunteers. Consequently there is a growing need for in vitro alternatives. The main goal of this project is the use of genomics (micro arrays) as a popular, innovative tool to gain better insight in the biochemical pathways of sensitization and irritation after exposure of a cell system to model sensitizing and irritating chemicals (the chemicals will be chosen, based on scientific literature). Micro arrays will at first be applied to dendritic cells, isolated from cord blood, to identify the genes that are of importance in the process of sensitization. To study the process of irritation, there will be a selection of a relevant cell system (Episkin, SkinEthic, Epiderm). Micro arrays are also used to study these pathways of irritation. Based on these micro array analyses we'll be able to identify the genes that can be used as a biomarker for the in vitro tests (probably under the form of dedicated arrays) for sensitization as well as for irritation. Finally, the in vitro tests can be applied in environmental toxicology: the identification of the potential sensitizing or irritating mechanism of environmental pollutants (PCB's, pesticides). This knowledge can be used in risk assessments.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Schoeters Elke

Research team(s)

Project type(s)

• Research Project

Abstract

This FWO scientific research network on gene therapy brings flemish (and belgian) laboratories active in the field of gene therapy together in order to stimulate the interaction, to exploit the complementarity of knowledge and technology between the participating partners, and to be able to compete with foreign research groups in the field. Research programs will be focused on both fundamental and clinical aspects of gene therapy.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Rationale and objectives Human myeloid dendritic cells (DC) are a rare leukocyte population that plays a crucial role in the initiation of a primary cell-mediated immune response. DC form a specialized network of antigen-capturing and antigen-presenting cells throughout the human body and DC can specifically activate naïve or quiescent CD4+ helper T cells and CD8+ cytotoxic T cells (CTL). Manipulation of DC with tumor antigens for the induction of tumor immunity is currently a 'hot topic' in experimental immunotherapy, and its purpose is to activate specific CTL, potent immune effector cells capable of recognizing and eliminating tumor cells. For an optimal stimulation of CD8+ CTL, the antigen should be endogenously synthesized in order to access the MHC class I presentation pathway. Therefore, genetic loading of DC with defined tumor antigens might be a useful strategy for the development of a DC-based tumor vaccine for several types of cancer. The Wilms' tumor (WT1) gene product has recently been characterized as an overexpressed leukemia-associated transcription factor which might be used as a tumor antigen for immunotherapy of acute leukemia (AL). In the present project, we propose to load DC from normal donors and leukemia patients with WT1 using either cDNA or mRNA transfection techniques in order to activate autologous WT1-specific cytotoxic T lymphocytes (CTL) in vitro. Furthermore, we want to study the origin, developmental pathways and growth requirements of the recently identified DC of lymphoid/plasmacytoid origin (DC2), starting from CD34+ hematopoietic progenitors and their potential use for DC-based immunotherapy. Methods Immature monocyte-derived DC will be loaded with WT1 by gene transfection or using whole tumor cells (using electrofusion, leukemic DC or phagocytosis of apoptotic AL cells). Afterwards, mRNA-transfected DC will be matured with tumor necrosis factor (TNF)-? and lipopolysaccharide (LPS). HLA-compatible WT1-specific CTL clones will be used to verify whether WT1-loaded DC present WT1-derived epitopes via MHC class I molecules. In a second phase, DC loaded with WT1 will be used in autologous settings in order to evaluate whether they can induce a primary antigen-specific CTL response in vitro. In order to determine this, autologous peripheral blood mononuclear cells (PBMC) will be cocultured with autologous mature DC loaded with WT1 in the presence of IL-7. Restimulations with autologous, mature DC loaded with WT1 will be performed weekly thereafter in the presence of IL-2 and IL-7, in order to expand antigen-specific CTL. CTL lysis assays (51Cr release or lactate dehydrogenase release assays) will be performed in order to examine the capacity to lyse autologous WT1-loaded DC or WT1-positive HLA-compatible target cells. In parallel to these experiments, we will phenotypically and functionally characterize of plasmacytoid DC, also called DC2, in different hematopoietic sources including bone marrow, peripheral blood and cord blood, using cell isolation and flow cytometric techniques. In addition, we will study the developmental pathway and growth regulation of DC2 precursors starting from CD34+ hematopoietic progenitors in order to develop culture protocols, which will allow more extensive use of this DC type for immunotherapeutic purposes.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Driessche Ann

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) as a potential cancer vaccine. Human dendritic cells (DC) from healthy individuals, treated cancer patients and HIV positive individuals will be cultured starting from peripheral blood monocytes. The major aim is to transfer defined tumor and HIV antigens to DC by means of transfection of DC with mRNA encoding defined antigens. Antigen-loaded DC will be used for induction of antigen-specific autologous cytotoxic T cells capable of eradicating autologous tumor cells or HIV-infected cells. In a later phase, DC will be loaded with unfractionated tumor antigens (total tumor mRNA, apoptotic tumor cells). This approach will be tested using tumor material derived from cervix cancer and lymphoma patients.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

Although tumor-specific antigens have been described for a number of cancers, the immune response to these antigens is often inexistent or deficient. One possible explanation for this deficient immune response is that tumor cells themselves do not function adequately as antigen presenting cells (APC). Therefore, gene transfer in dendritic cells (DC), which are very potent antigen presenting cells of the immune system, could be a useful strategy for tumor immunotherapy. In vitro cultured human dendritic cells will be transfected with mRNA encoding tumorassociated/specific geneproducts or uploaded with the full antigenic spectrum of tumorcells (tumorextracts, cellysates or total RNA). After cocultivation with autologeous CD8+ T-ceIls we will investigate if the cultured cytotoxic T-cells show a direct speci-ficity against tumorcells. The main purpose of these experiments is the development of a DC-based in vitro immunotherapy protocol for coloncancer, cervixcancer and lymphomas.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Ponsaerts Peter

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of the project is to induce a strong HIV-specific T-cell response, through loading of antigen-presenting cells (APC), more specific dendritic cells (DC) with Tat and/or Rev antigens, possibly in combination with Gag messenger RNA (mRNA). The ex vivo loading of autologous DC with Tat and/or Rev allows us to optimize the antigen dose, the DC type and the antigen loading method. Moreover, this method permits us to study the role of HIV-specific CD4+ Th1 cells at the induction and sustaining of a HIV-specific CTL effector response in vitro, at which CTL-mediated lysis of infected cells and eradication of the virus can be set as an endpoint.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Den Bosch Glenn A L

Research team(s)

Project type(s)

• Research Project

Abstract

Cervical cancer is the third most common cancer among women worldwide. Despite the progress in current therapies, these common treatments still have several disadvantages. On the one side is it impossible to remove all occurred micrometastases with surgery. On the other hand do radio- and chemotherapy not exclusively attack tumour tissue, but also exert a toxic effect on normal tissues and suppress the immune system. Therefore current research aims novel and more effective therapies. Loading dendritic cells with tumour antigens for the induction of anti-tumour immunity is at this moment a 'hot topic' of experimental immunotherapy. The principle of immunotherapy is to specifically stimulate the immune system for generating a tumour specific immune response. Cervical cancer is linked with human papilloma virus (HPV) infection. Although there are over 20 oncogenic HPV genotypes, HPV type 16 and 18 are the most prevalent in cervix carcinoma. The principle of a therapeutic vaccine consists in presenting HPV related antigens, such as E6 and E7 viral proteins, to professional antigen presenting cells (APC), especially dendritic cells (DC), to induce a strong T-cell response. The shape, in which the HPV antigens are presented to the DC, determines for a great part the type and the strength of the resulting T-cell response. The current challenge is determining the most efficient way in using modified DC in immunotherapeutic protocols . The generation of an optimal cellular anti-tumour response implies the activation of tumour specific CD8+ cytotoxic T-cells. However, more and more studies underline the important role of CD4+ T-cells in the regulation of the immune response. We aim in this project at the generation of a strong HPV specific CD4-positive as well as a CD8-positive immune response. For this purpose, we will generate cDNA constructs for the in vitro transcription of HPV 16 E6 and E7 mRNA, if necessary in combination with MHC class II signalling sequences (e.g. LAMP-I). The functionality of the produced mRNA shall be tested after transfection of DC with this mRNA. We will demonstrate protein expression with Western Blotting, while MHC class I and/or class II presentation of the antigenic peptides shall be tested with peptide-specific CD8+ or CD4+ T-cell clones. We shall also start with the development of an in vitro T-cell activation protocol for the generation of HPV 16 E6 and E7 specific T-cells with peptide pulsed DC. Furthermore, we shall start up an ex vivo study, more specific in the second term of the project, on the basis of the developed strategy during the first term. We will determine whether in vitro an autologous immune response can be elucidated against the tumour cells of a patient. For this purpose, we shall generate DC from peripheral blood samples of cervix carcinoma patients and modify these DC with mRNA coding for HPV antigens. After in vitro activation of autologous T-cells, we shall determine if there is sufficient reactivity against autologous tumour cells of the patients. The ultimate goal of these experiments is the development of an efficient strategy that can be used in a clinical model.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Cools Nathalie

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) as a potential cancer vaccine. Human dendritic cells (DC) from cancer patients will be cultured starting from peripheral blood monocytes. The major aim is to transfer tumor proteins from autologous tumor cells towards DC by means of transfection of DC with mRNA encoding defined antigens or with total tumor mRNA, or by pulsing of DC with apoptotic/necrotic tumor cells. Tumor antigen-loaded DC will be used for induction of tumor-specific autologous cytotoxic T cells ex vivo. As a first step, DC from cervix carcinoma patients will be loaded with mRNA encoding a single defined antigen (e.g. human papilloma virus E7 antigen) for ex vivo tumor vaccination against defined antigens. In a later phase, DC will be loaded with unfractionated tumor antigens (total tumor mRNA, apoptotic tumor cells). This approach will be tested using tumor material derived from lymphoma patients.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Lardon Filip
• Co-promoter: Van Bockstaele Dirk
• Co-promoter: Vermorken Jan

Research team(s)

Project type(s)

• Research Project

Abstract

It is clear that the current options used to treat cancer will not cure many patients suffering from that disease. There is a need for the development of new treatment strategies, based on concepts different from and/or complementary to the classical treatment modalities. In this interuniversity project, experimental work will be performed in order to investigate three promising research lines leading to new options in the treatment of cancer: immunotherapy using tumor peptides and/or dendritic cells, anti-angiogenic treatment and anti-lipogenic therapy.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Driessche Ann

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) for induction of tumor-specific autologous cytotoxic T cells in vitro in an immunotherapy model. In vitro generated DC will be either genetically modified by cDNA or mRNA transfection to express tumor-associated gene products, or loaded with the full antigenic spectrum of tumor cells, i.e. tumor extracts, cell lysates and total RNA. Loading methods will first be optimized in a melanoma tumor model. Afterwards, this knowledge will be applied for the development of a DC-based in vitro immunotherapy protocol for colon and cervix carcinoma.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The evaluation of the function or dysfunction of specific cells within a given organ requires in many cases the preceding viable isolation of these cells from a -sometimes- abundant amount of unwanted accessory cells. For this a number of cell separation techniques are available based on physical properties such as differences in cell density, cell adhesion, immunoaffinity etc' However, the flow cytometric cell sorting technique (based on electrostatic droplet formation) is the only separation technique that permits to separate different cell populations (up to 4) while simultaneously evaluating quite a number of properties such as size, internal complexity, DNA-content, presence or absence of up to 4 or 5 surface or cytoplasmic antigens. Since different cell populations may differ in subtle ways from others, this multiparametric flow cytometric sorting approach is in many cases a prerequisite to isolate the cells of interest: the primitive hematopoietic cell can only be defined by multiparametric labelling, kidney cell subpopulations, malignant versus normal cells, cell populations that are different in terms of cell cycle rate etc' It is clear that the availability of a cell sorter is a prerequisite for the four applying groups to study their respective cell(s) of interest. From 1990 onwards three of the four groups have built up expertise in the field, by joining forces and collaborating in the purchase of a FACStarPlus cell sorter. The output of numerous articles and several PhD theses may serve as proof of the good management of this interdisciplinary sorting facility. After 8 years of continuous heavy use, and in order to guarantee continuity in their research, the three initial groups, together with a fourth group (Tropical Medicine, Immunology) that meanwhile established close collaboration, now consider the purchase of a new generation cell sorter to be a priority. The growing number of users and applications have made the workload on the old instrument critically high. More elaborate simultaneous labelling and multiple and faster sorts are necessary to efficiently use the 'sometimes- scarce available starting material. This can only be accomplished by the new generation machines that guarantee much higher sort rates (up to > 30,000 cells/second, compared to 3000 cells/second on the old equipment) . Aerosol control systems implemented in the new machines offers prospects for work with potentially infectuous material (tropical medicine) The laser configuration of the old system is inadequate and the storage capacity and compatibility of the old computer system do not satisfy anymore the actual needs of a multi-user multidisciplinary facility. In what follows we will highlight the objectives and activities of the different research groups. It should be clear that no effort is made to link the respective topics: indeed the research topics described in this funding application are heterogeneous. Apart from some obvious common interests, the major link of these groups is the awareness that they all need cell sorting facilities to reach their goals.

Researcher(s)

• Promoter: Van Bockstaele Dirk
• Co-promoter: Berneman Zwi
• Co-promoter: De Broe Marc
• Co-promoter: D'Haese Patrick
• Co-promoter: Lardon Filip

Research team(s)

Project type(s)

• Research Project

Abstract

The project focuses on the use of antigen-modified human dendritic cells (DC) as a potential cancer vaccine. Human dendritic cells (DC) will be cultured in vitro starting from peripheral blood monocytes. The major aim is to transfer tumor proteins from the tumor cell towards DC by means of transfection of DC with total tumor mRNA or by pulsing of DC with apoptotic/necrotic tumor cells. Tumor antigen-loaded DC will be used for induction of tumor-specific autologous cytotoxic T cells in vitro. Using melanoma antigens as a model tumor antigens, loading methods will be studied and compared in their ability to elicit a primary immune response in vitro. Afterwards, this knowledge will be applied for the development of a DC-based cancer vaccine protocol for non-Hodgkin lymphoma and colon carcinoma.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Although tumor-specific antigens have been described for a number of cancers, the immune response to these antigens is often inexistent or deficient. One possible explanation for this deficient immune response is that tumor cells themselves do not function adequately as antigen presenting cells (APC). Therefore, gene transfer in dendritic cells (DC), which are very potent antigen presenting cells of the immune system, could be a useful strategy for tumor immunotherapy. In vitro cultured human dendritic cells will be transfected with mRNA encoding tumorassociated/specific geneproducts or uploaded with the full antigenic spectrum of tumorcells (tumorextracts, cellysates or total RNA). After cocultivation with autologeous CD8+ T-ceIls we will investigate if the cultured cytotoxic T-cells show a direct speci-ficity against tumorcells. The main purpose of these experiments is the development of a DC-based in vitro immunotherapy protocol for coloncancer, cervixcancer and lymphomas.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Ponsaerts Peter

Research team(s)

Project type(s)

• Research Project

Abstract

Dendritic cells have become the central player in the immune system. The effector cells such as B- and T-cells are regulated by the dendritic cells that act as initiator and modulator of the immune response. These cells are potent activators of naive T-cells, but can also tolerize T cells directed against self-antigens. Since these cells can now be obtained in sufficient numbers to allow the study of the physiology of these cells in different biological situations (allergy, transplantation, cancer) and their manipulation in vitro. They may become a powerful tool to manipulate the immune system.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The purpose of this research is to investigate the efficiency of gene transfer and gene expression in human hematopoietic cells by nonviral and viral transduction methods and study of factors influencing transduction efficiency in both gene transfer systems. The development of a dendritic cell based tumor vaccine is a potential consequence of this study.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Snoeck Hans
• Co-promoter: Van Broeckhoven Christine

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to investigate 1) in which stem cell populations gene transfer will lead to stable long term expression of the transfered genes in the different hematopoietic lineages (myeloid, T, B) and 2) which is the most efficient method of gene transfer (adeno-associated virus, liposomes, lipofectine) and which are the most efficient promotors to obtain stable long term expression of the transfered genes (CMV IE promotor, HSV-1 thymidine kinase promotor, c-kit promotor, CD34 promotor. Target cells for hematopoietic gene therapy will be CD34++ CD38- cells, which are known to very primitive cells, or subpopulations thereof. Culture assays used will be the pre-CFC assay and fetal thymus (SCID).

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Van Broeckhoven Christine
• Fellow: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

There are two main objectives in this study: first, the effects of different growth factors and inhibitors on subpopulations of human hematopoietic stem cells, derived from ontogenetic different sources, will be investigated. Next, we will examine whether these subpopulations can be used as targets for gene therapy and whether they can be transduced using adeno-associated virus. The following techniques will be used: flow-cytometry, in vitro cell culture, gene transduction, DNA- and RNA-PCR.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Weekx Steven

Research team(s)

Project type(s)

• Research Project

Abstract

There is a public concern about the possible role of pesticides in the development of certain diseases e.g. all kinds of allergy. From some pesticides it is kwown that they are heamatotoxic and influence the immune system. Most measurements of these effects of environmental agents have been made in animal models prior to use in humans. Recently there is a growing interest to assess effects in vitro. The aim of the project is to set up a battery of in vitro tests covering the different blood cell lineages. Special attention will go to the properties of dendritic cells, because they play an important role in the induction of some allergies.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: De Smedt Ann Ca

Research team(s)

Project type(s)

• Research Project

Abstract

Leukemic cells from patients with acute myeloid leukemia will be grown in culture. Attempts will be made to grow them long term and to establish whether this leads to a higher detection grade of karyotypic anomalies in AML.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The purpose of this research proposal is to introduce tumor-specific antigens (e .g . Melan-A, MAGE-3) into human dendritic cells (DC) for the activation of naive autologous CD8+ cytotoxic T cells. Therefore, we want to set up a gene transfer protocol in which DC will be genetically modified in order to express tumor-specific antigens and to present these antigens via the major histocompatibility complex class-I molecules on the surface of the DC. As DC are the most potent antigen-presenting cells - in contrast to tumor cells - this particular manipulation of DC would be an ideal strategy to induce tumor-specific cytotoxic T cells.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

There are two main objectives in this study: first, the effects of different growth factors and inhibitors on subpopulations of human hematopoietic stem cells, derived from ontogenetic different sources, will be investigated. Next, we will examine whether these subpopulations can be used as targets for gene therapy and whether they can be transduced using adeno-associated virus. The following techniques will be used: flow-cytometry, in vitro cell culture, gene transduction, DNA- and RNA-PCR.

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Weekx Steven

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to manipulate in vitro generated dendritic cells, cells with a very efficient antigen presenting capacity, in order to generate tumor specific cytotoxic T-cells.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to investigate 1) in which stem cell populations gene transfer will lead to stable long term expression of the transfered genes in the different hematopoietic lineages (myeloid, T, B) and 2) which is the most efficient method of gene transfer (adeno-associated virus, liposomes, lipofectine) and which are the most efficient promotors to obtain stable long term expression of the transfered genes (CMV IE promotor, HSV-1 thymidine kinase promotor, c-kit promotor, CD34 promotor. Target cells for hematopoietic gene therapy will be CD34++ CD38- cells, which are known to very primitive cells, or subpopulations thereof. Culture assays used will be the pre-CFC assay and fetal thymus (SCID).

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

The main objectives of this project are the elucidation of the role played by specific viral cofactors in AIDS and the identification of cofactor-targeted therapeutic approaches that could delay or prevent the progression of the immunodeficiency which is characteristic of AIDS.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to study cell proliferation in plant and animal cells by using nucleorides and nucleoride analogs an to study mutagenesis by DNA adduct formation.

Researcher(s)

• Promoter: Van Onckelen Harry
• Co-promoter: Berneman Zwi
• Co-promoter: Slegers Herman

Research team(s)

Project type(s)

• Research Project

Abstract

We will study the efficiency of transduction in various hematopoietic cells, as well as the efficiency of expression after transduction, depending on different promotors. The use of different promotors will enable to observe wheter there is a preferential expression of the transduced gene in the various cells that one wishes to influence by gene-therapy; hematopoietic cells.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Hendriks Lydia
• Co-promoter: Van Broeckhoven Christine

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to investigate 1) in which stem cell populations gene transfer will lead to stable long term expression of the transfered genes in the different hematopoietic lineages (myeloid, T, B) and 2) which is the most efficient method of gene transfer (adeno-associated virus, liposomes, lipofectine) and which are the most efficient promotors to obtain stable long term expression of the transfered genes (CMV IE promotor, HSV-1 thymidine kinase promotor, c-kit promotor, CD34 promotor. Target cells for hematopoietic gene therapy will be CD34++ CD38- cells, which are known to very primitive cells, or subpopulations thereof. Culture assays used will be the pre-CFC assay and fetal thymus (SCID).

Researcher(s)

• Promoter: Berneman Zwi
• Fellow: Van Tendeloo Vigor

Research team(s)

Project type(s)

• Research Project

Abstract

The main objective of this study was to characterize the kinetic status of the hematopoietic progenitor cell compartment. Differences in replicative capacity and cyclin properties were measured using special flow cytometric techniques, i.e. DNA distribution analysis, measuring of cyclin content, and the BrdU-Hoechst quenching technique.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

The aim of this project is to investigate 1) in which stem cell populations gene transfer will lead to stable long term expression of the transfered genes in the different hematopoietic lineages (myeloid, T, B) and 2) which is the most efficient method of gene transfer (adeno-associated virus, liposomes, lipofectine) and which are the most efficient promotors to obtain stable long term expression of the transfered genes (CMV IE promotor, HSV-1 thymidine kinase promotor, c-kit promotor, CD34 promotor. Target cells for hematopoietic gene therapy will be CD34++ CD38- cells, which are known to very primitive cells, or subpopulations thereof. Culture assays used will be the pre-CFC assay and fetal thymus (SCID).

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Analysis of cell physiological and proliferative changes of human hematopoetic stem-/progenitor cells exposed to molecules relevant for megakryopoieses and hematoprotection.

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Van Bockstaele Dirk

Research team(s)

Project type(s)

• Research Project

Abstract

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Hematopoietic stem cell activation and/or proliferation status and its commitment to either self renewal or differentiation is regulated by a combination of hematopoietic growth- and inhibitory factors. The immediate cel kinetic effects of a number of these factors (IL3, IL4, IL10, G-CSF, GM-CSF, SCF) will be investigated by means of the flow cytometric BrdU-Hoechst quenching assay.

Researcher(s)

• Promoter: Berneman Zwi

Research team(s)

Project type(s)

• Research Project

Abstract

Study of normal and dysplastic bone marrow in culture under the influence of HGF. Influence of lymphokines and lymphoid subpopulations on progenitorcells. Study of proliferation associated antifens and cellkinetic parameters

Researcher(s)

• Promoter: Berneman Zwi
• Co-promoter: Peetermans Marc
• Co-promoter: Snoeck Hans

Research team(s)

Project type(s)

• Research Project