Immune effector cell therapy for hematological malignancies with a focus on acute myeloid leukemia and multiple myeloma. 01/10/2019 - 30/09/2024

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)

Research team(s)

Vaccine & Infectious Diseases Excellence in Antwerp: Infectious disease prevention, control and management in a One Health policy context (VAX-IDEA). 03/07/2019 - 31/12/2023

Abstract

Infectious diseases (ID) and antimicrobial resistance (AMR) pose a continuous and serious threat to humans and animals (One Health). Five research units from the UAntwerpen, with strong international records and collaboration, will continue to jointly capitalize on their ID expertise. EVECO studies distribution, evolution and ecology of pathogens (plague, arenaviruses, …) and wildlife hosts, offering insights for emerging ID management. LMM has established large consortia (COMBACTE, PREPARE) leading to pan-European infrastructures for ID and antimicrobial consumption research. Next to developing rapid diagnostics, LMM investigates AMR mechanisms and pathogen dynamics in vitro, in humans/livestock, and in animal models to study host-immune response (biomarker discovery) and bacterial pathogenicity. LEH performs cutting-edge research on cell-based immunotherapies, in collaboration with the UZA Center for Cell Therapy & Regenerative Medicine. LEH investigates host-immune responses in vaccine trials using multi-parametric flow cytometry and systems biology to discover novel immune correlates of protection in next-generation vaccines. CEV studies the epidemiology of vaccine-preventable diseases and performs state-of-the-art vaccine trials with large national/international networks, including maternal immunization trials and quarantine studies with genetically-modified polioviruses. Given the global need for EID vaccines (Lassa, Ebola, …) , CEV engages in several innovative (non)-human challenge-phase 1-2 studies. CHERMID undertakes methodological and applied research on the intersection between health economics, biomedicine and mathematics. CHERMID is internationally renowned for developing models of dynamic ID processes within and between hosts and integrating these with cutting edge economic models. By integrating these complementary expertises, this COE will address current and future challenges in ID management.

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Unlocking the TCR repertoire for personalized cancer immunotherapies. 01/01/2019 - 31/12/2022

Abstract

Cancer is one of the leading causes of death worldwide. Over the past decades, new therapies have been developed that target the patients' immune system to mount an antitumor response. The efficacy of these immunotherapies has already been demonstrated in various clinical trials. Nevertheless, these therapies show a large variation in their individual responses as some patients respond well to the therapy, while others do not. In this project, we will investigate the differences between the T cell receptor (TCR) repertoires of responders and non-responders as a possible marker for immunotherapy responsiveness. We will apply state-of-the-art data mining methods and newly developed immunoinformatics tools to uncover those features that make a patient a clinical responder or non-responder. This will reveal the underlying mechanism of DC-based vaccine responsiveness. This can potentially accelerate general health care in terms of personalized medicine and will save costs.

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Improved RNA-based engineering of T lymphocytes with leukemia-specific T cell receptors to redirect their effector functions: towards a clinically safe platform to evaluate efficacy and potential off-target toxicity. 01/01/2018 - 31/12/2021

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.

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An interdisciplinary study on the role of the HLA genes and T-cell diversity as risk factors for herpes zoster. 01/01/2018 - 31/12/2021

Abstract

Chickenpox is a consequence of primary infection of varicella-zoster virus (VZV). Afterwards, VZV remains latent in neural ganglia until symptomatic reactivation called herpes zoster (HZ, shingles). In this project, we will first develop a novel computational framework that will allow us to estimate the probability that a pathogen-derived antigen is adequately recognised by the major histocompatibility complexes (MHC) encoded by HLA genes. Antigen bounding by MHC molecules is a necessary step prior to recognition (and further management) of infected cells. Next, we will obtain HLA data from 150 HZ patients and 150 matched controls. This will allow us to estimate whether and which HLA A/B/C genes are enriched or depleted in HZ patients. Our computational framework will allow us to estimate which VZV proteins are most likely of importance in controlling VZV. We will assess whether the HLA data is readily translated into the diversity of the T-cell receptor (TCR) against VZV, and against which of the most important VZV proteins. Finally, we will differentiate blood-derived inducible pluripotent stem cells (iPSC) into neuronal cells, infect these neuronal cells with VZV and study whether depletion of VZV-specific T-cells affects VZV proliferation, thereby confirming our earlier obtained HLA-TCR predictions.

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Preclinical development of a next-generation CAR-T cell therapy for multiple myeloma. 01/11/2019 - 31/10/2020

Abstract

In Belgium, two patients receive the diagnosis of multiple myeloma (MM) each day. Despite considerable therapeutic advances over the past decades, MM remains incurable. Drug resistance often leads to refractory disease and relapses. Therefore, there is an urgent need for novel treatment methods for MM. Immunotherapy has become an important asset in the treatment of various cancers, including MM. Chimeric antigen receptor (CAR)-T cell therapy has attracted much attention in recent years, most notably in B cell malignancies (BCMA). CAR-T cells are T lymphocytes that are genetically modified, predominantly by lentiviral or retroviral transduction, to express a CAR that can recognize virtually any surface epitope expressed on a cell. Results of early-phase clinical trials in MM, mainly targeted towards B cell maturation antigen, were promising with high clinical response rates, including complete responses. Unfortunately, responses are usually temporary and relapses have been described due to loss of BCMA expression following CAR-T therapy. In addition, serious adverse events that usually require hospitalization such as cytokine release syndrome are frequently reported. Hence, there is a general consensus that CAR-T cell-based immunotherapy can only become a "viable" therapeutic option in the future if these 3 challenges are adequately addressed: improving efficacy (challenge 1) while reducing toxicity (challenge 2) and costs (challenge 3). The general objective of this project is to develop a next-generation CAR-T cell treatment for multiple myeloma (MM). The hypothesis of this study is that targeting multiple antigens will broaden the anti-tumor immune response and, thus, enhance efficacy of the treatment by reducing the chance of immune escape. Incorporation of immune checkpoint downregulation and enhancement of their co-stimulatory and migratory function can potentially further augment the anti-tumoral properties of the CAR-T cells. Considering potential adverse events, we envisage mRNA electroporation and the use of gamma/delta (γδ) T cells as improvements to the safety and overall costs of CAR-T cell therapy. In summary, we envision a more effective, safer and economically viable CAR-T cell therapy.

Researcher(s)

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Preclinical development of a next-generation CAR-T cell therapy for multiple myeloma. 02/07/2019 - 01/07/2020

Abstract

Multiple myeloma (MM) is an malignancy that remains incurable to date. Chimeric antigen receptor (CAR)-T cell therapy has obtained impressive clinical results in leukemia and lymphoma, and is gaining momentum in MM as well. This project aims to tackle shortcomings in efficacy and safety in current CAR-T cell therapies by targeting multiple MM antigens, reducing T cell exhaustion and exploring alternative T cell subsets. Importantly, transient T cell modification ensures patient safety, reduces manufacturing costs significantly and can serve as an early-phase testing platform for clinical translation of novel CAR-T cell therapies.

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Harnessing the expression of interleukin-15 and CD56 in immunotherapeutic strategies combating leukemia: a functional and mechanistic characterization 01/10/2017 - 12/05/2019

Abstract

The "Breakthrough of the Year" of 2013, awarded by Science, was the burgeoning field of cancer immunotherapy. In spite of some great results, the search continues towards an ideal functioning of our immune cells, leaving a paramount question unanswered: can we identify specific cellular attributes denoting optimal activation and immune performance in combating cancer? In this project we will investigate the interleukin (IL)-15-mediated activation of immune cells, more specifically dendritic cells (DCs) and gd T cells, and their expression of CD56 in a model of acute myeloid leukemia. First, IL-2 and IL-15 will be compared for their immunostimulatory effect on gd T cells, conceivably strengthening the use of IL-15 in, among other, adoptive immunotherapy protocols. Induction of activation and enhancement of effector functions of gd T cells by these cytokines will be correlated with their CD56 expression. Next, we will delineate the cross-talk between our CD56+ and IL-15 expressing IL-15 DCs and gd T cells. Furthermore, the role of CD56 on these immune cells will be unraveled. This will give us the opportunity to finally answer the question whether CD56 expression is being indicative of an activated state, whether it actively leads to tumor cell killing and whether or not homodimeric interactions do play a role. Finally, mechanistic insight will be gained into the individual contribution of the IL-15 signaling pathways in induction of CD56 expression and immune cell activation.

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Maximizing the anti-tumor potency of next-generation dendritic cell vaccines by combining interleukin-15 and in situ silencing of programmed-death ligands. 01/01/2017 - 31/12/2020

Abstract

Currently therapeutic cancer vaccines have taken center stage in cancer immunotherapy. Such cancer vaccines are designed to delay or prevent cancer relapse after standard treatment with chemotherapy or radiotherapy, and to attack distant metastatic cancer cells. We have already successfully tested a personalized cell-based cancer vaccine for leukemia patients and we demonstrated that the vaccine could prevent leukemia relapse in about 35% of the vaccinated leukemia patients. This cancer vaccine consists of specially cultured immune cells of the patient that upon injection in the skin starts off an anti-tumor immune response against residual or chemotherapy-resistant leukemia cells. In this project we aim to make this personalized leukemia vaccine even more powerful in the test tube by innovative manipulations and by implementing new emerging anti-cancer strategies that have already proven successful in solid tumors.

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Research team(s)

Wilms' tumor 1-specific T cell receptor (TCR) RNA-modified T cells for adoptive immunotherapy of cancer : moving towards clinical application. 01/01/2017 - 31/12/2018

Abstract

The extraordinary specificity of T cells for their antigen turns them into an attractive cancer therapeutic. The use of TCR-redirected T cells is an innovative approach that could instantaneously confer anti-tumor specificity to a large number of effector T cells for adoptive immune therapy. However, the clinical efficacy of TCR-redirected T cells is still not satisfactory, and adverse effects have been observed. Therefore, the development of safer TCR-modified T cell strategies targeting universal tumor-associated antigens is necessary to broaden the clinical application of this immunotherapeutic strategy for cancer treatment. In our view, this research project will ultimately progress the cancer immunotherapy field as we will develop a clinically applicable technology to generate TCR-redirected T cells with an improved biosafety profile. Furthermore we will identify a set of patient-derived ' WTl-specific TCRs that could be exploited as generic molecular therapeutics for automated adoptive therapy of cancer patients with WTl-positive cancers.

Researcher(s)

Research team(s)

    Harnessing the expression of interleukin-15 and CD56 in immunotherapeutic strategies combating leukemia: a functional and mechanistic characterization. 01/10/2015 - 30/09/2017

    Abstract

    The "Breakthrough of the Year" of 2013, awarded by Science, was the burgeoning field of cancer immunotherapy. In spite of some great results, the search continues towards an ideal functioning of our immune cells, leaving a paramount question unanswered: can we identify specific cellular attributes denoting optimal activation and immune performance in combating cancer? In this project we will investigate the interleukin (IL)-15-mediated activation of immune cells, more specifically dendritic cells (DCs) and gd T cells, and their expression of CD56 in a model of acute myeloid leukemia. First, IL-2 and IL-15 will be compared for their immunostimulatory effect on gd T cells, conceivably strengthening the use of IL-15 in, among other, adoptive immunotherapy protocols. Induction of activation and enhancement of effector functions of gd T cells by these cytokines will be correlated with their CD56 expression. Next, we will delineate the cross-talk between our CD56+ and IL-15 expressing IL-15 DCs and gd T cells. Furthermore, the role of CD56 on these immune cells will be unraveled. This will give us the opportunity to finally answer the question whether CD56 expression is being indicative of an activated state, whether it actively leads to tumor cell killing and whether or not homodimeric interactions do play a role. Finally, mechanistic insight will be gained into the individual contribution of the IL-15 signaling pathways in induction of CD56 expression and immune cell activation.

    Researcher(s)

    Research team(s)

      Predicting Immune responses by Modeling immunoSequencing data (PIMS). 01/01/2015 - 31/12/2018

      Abstract

      Vaccine trials study the changes in vaccine-induced antibodies and T-cells and their protective value against natural infection. As such it has been noted that not all vaccines are equally effective and that variability exists between individuals in the magnitude and duration of the immune response after vaccination. We hypothesize that individual-specific genetic characteristics collected in a short time-window after vaccination are sufficient to predict immune responses for a long time period after vaccination. In this project we will recruit 120 individuals: 40 individuals will receive de novo and booster hepatitis B vaccination, 40 individuals will receive a monovalent measles booster vaccine and 40 individuals will receive a combined measles-mumps-rubella booster vaccine. The participants will undergo sampling on different time points (up to one year after vaccination). We will assess the changes in the expression of genes (transcriptomics) in immune-competent cells following vaccination, the individual-specific genetic predisposition for peptide recognition by T-cells (T-cell receptor and major histocompatibility sequencing), and adaptive immune responses (peptide-specific T-cells, antibodies) after vaccination. We will use advanced longitudinal modeling, data mining and machine learning techniques that will allow us to predict T-cell responses by means of the collected individual-specific data over long time periods. Through this project we will set the standard for Next-Generation Vaccinology. Importantly, our results will also be applicable to other fields of research such as therapeutic cancer vaccination and viral immunology.

      Researcher(s)

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        Project website

        CD56+ human blood dendritic cells: unique mediators of strong natural killer and gamma/delta T cell activation to promote antigen-specific T cell immune responses in health and disease. 01/01/2015 - 31/12/2018

        Abstract

        Human blood contains several immune-competent cells including cells of the innate and adaptive immune system. Over the past years, the phenotypic and functional boundaries distinguishing the main cell subsets of the immune system have become increasingly blurred. While it has been already established that T cells may share some phenotypic and functional features of natural killer (NK) cells, more recent evidence points to the existence of such overlap between NK cells and dendritic cells (DCs). Both NK cells bearing DC markers and antigen-presenting capacity and DCs expressing NK-related molecules and having cytotoxic functions have been described. In view of this, CD56, a prototypic marker of NK cells, was found to be expressed on DC derived from monocytes exposed to interleukin-15. We demonstrated that these IL15-DC were endowed with superior stimulatory and unique cytotoxic properties (killer DC). The aim of this project is to identify and characterize in detail the in vivo counterpart of these CD56+ killer DCs in human blood. Particular emphasis will be given to the reciprocal interactions of myeloid CD56+ DC-like cells with CD56+ innate lymphocytes (NK and NKT cells, γδ T cells) in the presence or absence of immunomodulatory molecules. Next, the capacity of CD56+ blood DCs to stimulate both innate and adaptive cell responses will be analyzed in a human acute myeloid leukemia (AML) model as a first step towards design of next-generation therapeutic AML vaccines.

        Researcher(s)

        Research team(s)

          CD56+ human blood dendritic cells: unique mediators of strong natural killer and gamma-delta T cell activation to promote antigen-specific T cell immune responses in health and disease. 01/01/2014 - 31/12/2017

          Abstract

          CD56+ myeloid blood DC constitute a unique and potent accessory cell type to promote and/or restore innate lymfocyte activation (NK and γδ T cells) and are superior to conventional myeloid DC for the induction of (tumor) antigen-specific T cell responses. The overall objective of the project is to to investigate the immunobiology of CD56+ DC-like in human blood cells of healthy individuals and of AML patients.

          Researcher(s)

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            Preclinical development of an innovative immune therapy based on CD56 + dendritic cells and interleukin-15: recruitment of the innate immune system in the fight against cancer. 01/01/2014 - 30/09/2015

            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)

            Research team(s)

              A quantitative analysis of varicella-zoster virus infection: from immunology to epidemiology. 01/10/2013 - 31/07/2015

              Abstract

              It is our goal to conceptualise mathematical models that describe the basic immunology with regard to varicella-zoster virus (VZV) and immunological perturbations caused by VZV at the individual level. Furthermore, at the population based level we will formulate mathematical models describing the transmission of VZV between individuals. Simulations of both withinhuman and between-human dynamics will be based on biological and epidemiological parameters. These parameters will be estimated from our previous studies, and other international studies, as well as this project's experimental study, which is designed to provide major insights in the immunology of latency and reactivation. More specifically, we will longitudinally assess the immune response of about 120 VZV immune persons whose immune systems were recently perturbed for different reasons such as re-exposure to VZV and reactivation of VZV as shingles (Herpes Zoster). In an innovating way we will also perform similar analyses in 30 healthy individuals thereby creating a control group and defining a benchmark for longitudinal variation in immunity. The biological parameters will be implemented in our newly developed mathematical models after thorough statistical analysis. For the first time in this field, we will apply certain advanced statistical techniques (nonlinear mixed and growth mixture models).

              Researcher(s)

              Research team(s)

                Reciprocal cross-talk between human natural killer cells and interleukin-15-cultured dendritic cells for improved anti-leukemic cytotoxic activity. 01/01/2013 - 31/12/2014

                Abstract

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

                Researcher(s)

                Research team(s)

                  Quantification of Wilms tumor gene (WT1) transcripts and of immune activation to monitor the therapeutic efficacy of denditric cell vaccination in acute myeloid leukemia. 01/09/2012 - 31/08/2015

                  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)

                  Research team(s)

                    T cell immunogenicity of RHAMM and BMI-1: towards a multi-antigen dendritic cell vaccine for hematological malignancies. 01/01/2012 - 31/12/2015

                    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)

                    Research team(s)

                      BOF: 1 year fellowship (Nathalie Deckx). 01/01/2012 - 31/12/2012

                      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)

                      Research team(s)

                        A quantitative analysis of varicella-zoster virus infection: from immunology to epidemiology. 01/10/2011 - 30/09/2013

                        Abstract

                        It is our goal to conceptualise mathematical models that describe the basic immunology with regard to varicella-zoster virus (VZV) and immunological perturbations caused by VZV at the individual level. Furthermore, at the population based level we will formulate mathematical models describing the transmission of VZV between individuals. Simulations of both withinhuman and between-human dynamics will be based on biological and epidemiological parameters. These parameters will be estimated from our previous studies, and other international studies, as well as this project's experimental study, which is designed to provide major insights in the immunology of latency and reactivation. More specifically, we will longitudinally assess the immune response of about 120 VZV immune persons whose immune systems were recently perturbed for different reasons such as re-exposure to VZV and reactivation of VZV as shingles (Herpes Zoster). In an innovating way we will also perform similar analyses in 30 healthy individuals thereby creating a control group and defining a benchmark for longitudinal variation in immunity. The biological parameters will be implemented in our newly developed mathematical models after thorough statistical analysis. For the first time in this field, we will apply certain advanced statistical techniques (nonlinear mixed and growth mixture models).

                        Researcher(s)

                        Research team(s)

                          The immune-modulating role of vitamin D3-treated dendritric cells in multiple sclerosis. 01/01/2011 - 31/12/2013

                          Abstract

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

                          Researcher(s)

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                            Feasibility and safety of a WT1-targeted cancer vaccine in patients with malignant mesothelioma and locally advanced breast cancer: an open label phase I trial. 01/01/2011 - 31/12/2013

                            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)

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                              Induction of multiple sclerosis (MS)-specific immune toleration using tolerogene dendritic cells and regulatory T cells. Preclinical evaluation of the therapeutic potential of cellular immune therapy in MS. 01/01/2011 - 31/12/2012

                              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)

                              Research team(s)

                                Boosting the cross-talk between human dentritic cells and natural killer cells by Toll-like receptor ligand-loaded leukemia cells for optimal anti-leukemia T cell responses. 01/01/2011 - 31/12/2012

                                Abstract

                                Both innate and adaptive immune responses can contribute to the eradication of acute myeloid leukemia (AML) cells, with natural killer (NK) cells and cytotoxic T cells (CTL) as the key players respectively. Dendritic cells (DC) bridge innate and adaptive immune responses by interaction with NK cells and cross-presentation of leukemia-associated antigens (e.g. VVTI) to T cells. Tolllike receptor (TLR) ligands were recently identified as important danger signals recognized by both DC and NK cells. Here, we want to examine if boosting the cross-talk between human dendritic cells and natural killer cells through exposure to TLR3/7/8 ligand-loaded AML cells leads to better anti-tumor T cell responses in vitro. More specifically, we will investigate whether the in vitro immunostimulatory of human dendritic cells and their cross-presentation capacity to T cells increase in the presence of NK cells and TLR3/7/8 ligand-loaded AML cells.

                                Researcher(s)

                                Research team(s)

                                  Boosting the cross-talk between human dendritic cells and natural killer cells by Toll-like receptor-ligand-loaded leukemia cells for optimal anti-leukemia T cell responses. 01/01/2011 - 31/12/2011

                                  Abstract

                                  Currently, targeting both NK cells and DC for immune-based therapy is advised to improve their cross-talk and exert strong specific anti-tumor T cell responses. Therefore, the rationale of this study is to make AML cells more immunogenic for both DC and NK cells. In this respect, Toll-like receptor (TLR)-ligands were recently identified as important danger signals recognized by both DC and NK cells. Exciting results on the DC and NK cell stimulatory capacity of AML cells transfected with the synthetic TLR3-ligand polyriboinosinic polyribocytidylic acid [poly(I:C)], point tohold promise for their potential to boost the NK-DC cross-talk and subsequent anti-tumor T cell responses. To this end, we will further investigate the immunostimulatory capacity of DC and their cross-presentation capacity to T cells in the presence of NK cells and poly(I:C)-loaded AML cells.

                                  Researcher(s)

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                                    Clinical and preclinical research of the effect of cellular mediators on the modulation of pathogenic responses in multiple sclerosis. 01/01/2009 - 31/12/2012

                                    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)

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                                      Becton Dickinson FACSAria II: highspeed, fixed alignment benchtop cell sorter platform. 19/12/2008 - 18/12/2013

                                      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)

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                                        Stimulation of innate immune responses targeted against acute myeloid leukemia cells after exposure to Toll-like receptor ligands, with a view to the development of a leukemia vaccin. 13/10/2008 - 12/10/2009

                                        Abstract

                                        This project will contribute to the development of immunotherapy as adjuvant therapy for leukemia patients. The aim of immunotherapy of leukemia is the elimination of residual leukemic cells by activated immune cells, resulting in an increased survival for leukemia patients after standard therapy. In this project, human acute myeloid leukemia (AML) cells are loaded with immunostimulatory danger signals, more specifically Toll-like receptor ligands. We investigate the direct effects of TLR ligands on AML cells, as well as the capacity of TLR ligand-loaded AML cells to activate immune cells and to induce innate and/or adaptive immune responses. Previous results of experiments performed in our laboratory showed that the immunogenicity of AML cells increased when the AML cells were loaded intracellularly with the synthetic TLR3 ligand poly(I:C) by means of electroporation. Besides, dendritic cells (DC) and natural killer cells were activated by poly(I:C)-electroporated AML cells. In the next phase, we will investigate if poly(I:C)-electroporated AML cells are also able to induce differentiation of monocytes towards immunostimulatory DC. Furthermore, we will examine the direct effects of another TLR ligand, the TLR7/8 ligand resdiquimod, on AML cells. This in vitro research is an essential step in determining how TLR ligands can be useful for immunotherapeutic purposes. In this way, this project will contribute to the improvement of immunotherapy of AML and other tumor types.

                                        Researcher(s)

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                                          Effect of innate immune signals on leukemia cells for the stimulation of natural killer cells and T helper type 1-polarizing dendritic cells. 01/01/2008 - 31/12/2011

                                          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)

                                          Research team(s)

                                            Cellular immunology in cancer and HIV, and multidisciplinary cell therapy research and clinical studies. 01/10/2007 - 30/09/2017

                                            Abstract

                                            My research plan focuses on the establishment of a cellular immunology research unit within the Laboratory of Experimental Hematology studying the immunobiology of dendritic cells and molecular modulation of their function in vitro and in vivo for applications in cancer and infectious disease models (HIV, CMV). This translational research is also being translated to clinical application in early phase I/II clinical trials perfomed at the Center for Cellular Therapy and Regenerative Medicine (CCRG) of the Antwerp University Hospital of which I am the scientific director. At the CCRG, I will instigate other experimental cell therapy applications in collaboration with Cardiology and Ophthalmology as well as established stem cell therapy applications in the field of hematological malignancies.

                                            Researcher(s)

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                                              Inhibition of human immunodeficiency virus (HIV) replication. 01/01/2007 - 31/12/2011

                                              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)

                                              Research team(s)

                                                Study of in vivo and in vitro modulation of dendritic cells in Th1 (rheumatoid arthritis) and Th2 (venom allergy) mediated diseases. Influence of anti-TNF and immunotherapy. 01/01/2006 - 31/12/2009

                                                Abstract

                                                Researcher(s)

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                                                  Induction of immunity by dendritic cells in cancer and aids. 01/01/2005 - 31/12/2008

                                                  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)

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                                                    Preclinical design of RNA-modified dendritic cell vaccines for cancer and HIV 01/10/2004 - 30/09/2007

                                                    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.

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                                                      Feasibility of dendritic cell immunotherapy for cancer using the Wilms' tumor WT1 protein as a candidate universal tumor antigen. 23/01/2004 - 22/01/2007

                                                      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.

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                                                        Differentiation from stem cells to functional neuron cell: in vitro and in vivo model for the treatment of traumatic brain and spinal injuries of children. 01/07/2003 - 30/06/2007

                                                        Abstract

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                                                        Induction of cellular immunity against the regulatory gene products Tat and Rev as a means to eradicate HIV. 01/01/2003 - 31/12/2006

                                                        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)

                                                        Research team(s)

                                                          Preclinical design of RNA-modified dendritic cell vaccines for cancer and HIV 01/10/2001 - 30/09/2004

                                                          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)

                                                          Research team(s)

                                                            Efficiency of gene therapy in human hematopoietic stem cells. 01/10/1998 - 30/09/2000

                                                            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)

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                                                              Efficiency of gene therapy in human hematopoietic stem cells. 01/10/1996 - 30/09/1998

                                                              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)

                                                              Research team(s)

                                                                Efficiency of gene therapy in human hematopoietic stem cells. 01/10/1995 - 30/09/1996

                                                                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)

                                                                Research team(s)