Research Evelien Smits

Abstract

The quality of human (and veterinary) health care systems substantially depends on key innovations. Often, these were driven by the field of physics, followed by interdisciplinary and inter-sectorial actions in engineering, chemistry, biology, and medicine, such as X rays in medical diagnostics, ionizing radiation in cancer treatment, and femtosecond lasers for precision surgery. Medical gas plasma technology was introduced to human health care a decade ago. Today, accredited medical plasma devices are in daily operation in dozen dermatology centers in middle Europe to improve wound healing. In addition, physical plasmas were shown to inactivate cancerous cells. Actinic Keratosis is a skin disease affecting millions of Europeans and making them prone to invasive and deadly skin cancer. Many of the available treatment options are associated with low efficacy, pain, risks, and/or high costs. Medical gas plasma technology is operated at body temperature and applied painlessly, cost-effectively, and without notable side effects. Gas plasma has been suggested to be active on high-grade cancer cells, but its activity against premalignant cells, as in Actinic Keratosis, is unknown. By using beyond state-of-the-art plasma multijet technology, the primary technical objective of this project (PlasmACT – Plasma against Actinic Keratosis) is to support skin cancer prevention by medical gas plasma therapy of Actinic Keratosis. PlasmACT does so by educating a new generation of application-oriented scientists that are exposed to questions and findings from different scientific fields (interdisciplinary from physics over chemistry and biology to medicine) and capable of addressing questions in view of both academic as well as business needs (inter sectoral) while incorporated in a vivid and productive environment across borders and cultures (international).

Researcher(s)

• Promoter: Bogaerts Annemie
• Co-promoter: Smits Evelien

Research team(s)

• Plasma Lab for Applications in Sustainability and Medicine - Antwerp (PLASMANT)

Project website

Project type(s)

• Research Project

Abstract

Paediatric high-grade gliomas (pHGG) represent the leading cause of cancer-related death in childhood. With the current standard of care (SOC), the prognosis is very dismal with a 5-year survival rate of less than 20%. There is an urgent need to develop new treatment strategies to improve the overall survival. Immunotherapy to treat cancer is now considered to be one of the main pillars in cancer management and adoptive cell transfer has had enormous successes in the paediatric field in haematological malignancies. However, the therapeutic efficacy, as seen in haematological malignancies, has been lacking in solid tumours so far due to several challenges. pHGG are known for their cold immunological tumour microenvironment with few tumour infiltrating lymphocytes, have a high heterogeneity in antigen expression and are difficult to access due to the blood-brain barrier. Therefore, we aim to develop a novel therapy to overcome these challenges by combining the locoregional administration of our designed cell therapy with an immune priming strategy. We hypothesize that this combination therapy can increase the therapeutic efficacy of the SOC against pHGG.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite screening campaigns, 8,000 people in Belgium are diagnosed with colorectal cancer annually. Of these, 25% of patients already have metastases at the time of diagnosis, and an additional 40% will develop metastases during their disease progression. The treatment of patients in an advanced stage mainly relies on multi-drug chemotherapies that can be combined with targeted therapies, but with limited success. This group of patients therefore needs new, improved treatments. In colorectal cancer, there is a close interaction between tumor cells and the tumor microenvironment, of which cancer-associated fibroblasts are the most common cells. These are also involved in the formation, growth, and migration of the tumor and can form a shield around the tumor that hinders the effect of systemic therapies. However, it has been found that not all cancer-associated fibroblasts contribute to tumor progression, and it is important to selectively target them. In our lab, we have discovered a subgroup of cancer-associated fibroblasts with a high expression of CD70 that are more common in advanced stages and are clearly associated with tumor migration and immune suppression. We are convinced that targeting these CD70+ cancer-associated fibroblasts can improve the efficacy of chemotherapy. In this project, I aim to investigate whether a CD70-targeted immune cell therapy can significantly improve the effect of first-line chemotherapies using state-of-the-art 3D culture models and an in-house developed drug screen imaging platform.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van den Eynde Astrid

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The process of drug discovery has long been characterized by inefficiency, high costs, and a low success rate. Over the past few decades, the traditional drug discovery pipelines, which heavily rely on trial-and-error experimentation and extensive pre-clinical testing in 2D cell line models, has proven to be a lengthy and expensive endeavour. Moreover, the average timeline for bringing a new drug to the market ranges from 10 to 15 years, with development costs averaging around $2.6 billion per approved drug. Furthermore, the most significant issue arises when these molecules progress to clinical trials, where more than 90% of them demonstrate limited efficacy as monotherapy treatment, highlighting the recent development trend towards combination therapies. Nonetheless, this high rate of failure not only represents a significant financial burden but also delays the delivery of potentially life-saving treatments to those in need. Concerning the unmet need for more efficient drug development programs and more potent treatment strategies, we developed the OdeXAI discovery platform that integrates three innovative pillars namely: drug synergism, patientderived tumor organoids and AI-guided small molecule design. Using this integrated pipeline, we aim to efficiently develop novel small molecules that will work highly synergistic together with FDA approved drugs and in house developed small molecules. With this IOF-POC CREATE project, we aim to validate the efficiency of the OdeXAI drug discovery platform. If successful, this synergy-based AI-driven drug discovery engine will inevitably contribute to faster and more efficient future combination therapy development.

Researcher(s)

• Promoter: Deben Christophe
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type worldwide, with a majority of the patients progressing towards recurrent/metastatic HNSCC with limited treatment options. Despite the high natural killer (NK) cell infiltration, the efficiency of newly developed adoptive cellular therapies in clinical trials is limited. Therefore, I hypothesize that HNSCC cells secrete immunosuppressive metabolites in the tumor microenvironment (TME), exaggerated by the high level of hypoxia, inducing evasion to NK cells. Using physiologic and conditioned media at different oxygen levels, metabolic alterations in the TME are characterized by gas chromatography-mass spectrometry, providing high-value candidate metabolites that are later evaluated in a high-throughput screen to determine their effect on the NK cell killing capacity. Intracellular metabolic and functional changes of NK cells induced by exposure to the interfering metabolites are identified together with phenotypic profiling. Using an orthotopic humanized mouse model, NK cell functionality is investigated after modification of the TME and restoration of NK cell cytotoxicity combined with standard-of-care HNSCC treatment is evaluated. Concluding, this project will obtain fundamental insights into the suppressive role of hypoxia-induced metabolites on NK cells and will provide valuable knowledge for adoptive cellular therapies in development.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Fellow: Melis Jöran

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Paediatric high-grade gliomas (pHGG) represent the leading cause of cancer-related death in childhood. With the current standard of care (SOC), the prognosis is very dismal with a 5-year survival rate of less than 20%. There is an urgent need to develop new treatment strategies to improve the overall survival. Immunotherapy to treat cancer is now considered to be one of the main pillars in cancer management and adoptive cell transfer has had enormous successes in the paediatric field in haematological malignancies. However, the therapeutic efficacy, as seen in haematological malignancies, has been lacking in solid tumours so far due to several challenges. pHGG are known for their cold immunological tumour microenvironment with few tumour infiltrating lymphocytes, have a high heterogeneity in antigen expression and are difficult to access due to the blood-brain barrier. Therefore, we aim to develop a novel therapy to overcome these challenges by combining the locoregional administration of our designed cell therapy with an immune priming strategy. We hypothesize that this combination therapy can increase the therapeutic efficacy of the SOC against pHGG.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Van Audenaerde Jonas
• Fellow: Vanheeswijck Liesbeth

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite significant advancements in oncological treatments, many patients still succumb to the cancer, which remains the second leading cause of death worldwide. Novel treatment options are therefore urgently needed. The breakthrough of immunotherapy has revolutionized the field of oncology, however, the majority of patients remains unresponsive to immune checkpoint inhibitors. Armoured cellular therapies such as chimeric antigen receptor (CAR)-engineered T cells are now generating success in haematological malignancies, but comes with safety issues. Their lymphocytic counterpart, natural killer (NK) cells, are now presenting themselves as highly promising alternatives. Nonetheless, also NK cells remain ineffective against solid tumours. This is at least in part due to the hostile solid tumour microenvironment which impairs the metabolic and cytotoxic function of NK cells. Manipulating NK cells to withstand the vicious rigors of the tumour microenvironment could therefore be a gamechanger in their use as cell therapy against solid tumours. We discovered critical metabolic impairments in NK cells induced by tumour microenvironmental factors. We have found an actionable metabolic target to manipulate NK cells either pharmacologically or genetically, resulting in protection of their cellular health and cytotoxic function. With this IOF-POC project, we aim to validate and expand our patented claims in multiple solid tumour models on different levels and find industrial partners to proceed its valorisation route. Ultimately, our strategy to protect the fitness of NK cells in the tumour microenvironment could enable the efficacious application of CAR-engineered NK cell products for solid malignancies, and as such impact many cancer patients.

Researcher(s)

• Promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In this project we propose a radically new plasma based-methodology to both characterize as well as treat cancerous tissue (with a focus on melanoma). We will use plasma excitation (in combination with laser vibration measurements) for in-situ characterization of the visco-elastic mechanical properties of biomedical tissue. These mechanical properties will allow us to detect and monitor cancerous tissue. Furthermore, we will develop a novel controlled plasma cancer treatment method which integrates the in-situ material identification method in order to tune the plasma therapy.

Researcher(s)

• Promoter: Vanlanduit Steve
• Co-promoter: Bogaerts Annemie
• Co-promoter: Dirckx Joris
• Co-promoter: Smits Evelien

Research team(s)

• Industrial Vision Lab (InViLab)

Project type(s)

• Research Project

Abstract

The Vevo LAZR-X is an imaging platform for preclinical applications capable of acquiring in vivo anatomical, functional and molecular data. It combines ultra high frequency ultrasound with photoacoustic imaging (a new biomedical imaging modality based on the use of lasergenerated ultrasound) for high resolution images as well as software for analysis and quantification. This equipment will be used in the context of the study of (cardio)vascular diseases, genetics of the heart, heart valves and aortic dissection, kidney diseases and their effects on the heart and blood vessels, and for cancer research.

Researcher(s)

• Promoter: De Meyer Guido
• Co-promoter: De Keulenaer Gilles
• Co-promoter: Heidbuchel Hein
• Co-promoter: Loeys Bart
• Co-promoter: Smits Evelien
• Co-promoter: Van Craenenbroeck Emeline
• Co-promoter: Verhulst Anja
• Co-promoter: Verstraeten Aline

Research team(s)

• Physiopharmacology (PHYSPHAR)

Project type(s)

• Research Project

Abstract

In the past five years, RNA therapeutics have witnessed a true revolution. Several RNA-based therapies have been approved for the treatment of genetic diseases, with unprecedented successes, as in spinal muscular atrophy. Moreover, the past year showed the world that RNA-based therapies, namely mRNA vaccines, can be the answer to a worldwide pandemic and save the lives of millions. RNA therapies are however lagging behind in clinical oncology. The overarching aim of this multi-armed project is to develop RNA-based cancer treatments. In parallel, the development of immune checkpoint inhibitors has revolutionized cancer care, but its success remains limited to a subset of patients. Altogether, for 60 percent of the eight million new cancer patients diagnosed in Europe each year, including almost all children with solid tumors, there is no EMA- or FDA-approved immunotherapy option, and they are left out of the circle of hope. In response, CANCERNA aims to build on these two breakthroughs and apply RNA-based therapeutics to overcome key barriers to unfold successful anti-cancer immune responses. Our two key objectives are: on one hand, harness the modulation of RNA processing to enhance the accessibility and immune susceptibility of the tumour and its microenvironment. While on the other hand, enhance the activity of the immune system by retargeting immune effector cells and developing personalized mRNA vaccines. The project will focus on two cancer types: acute myeloid leukemia and uveal melanoma. The collective knowledge of our consortium of RNA scientists, clinicians and biotech-pharma experts in RNA processing, RNA drug design and delivery, biocomputing and immuno-oncology provides a unique opportunity to significantly advance novel RNA technologies into successful cancer therapies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Pauwels Patrick
• Co-promoter: Siozopoulou Vasiliki
• Co-promoter: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the third deadliest cancer worldwide with an increasing incidence. The 5-year survival of 7% has barely changed in 50 years and is stated as the worst of any cancer type. The immunosuppressive tumour microenvironment is believed to be the major confounding factor involved in failure of current therapies. Because of the high medical need, we will investigate the potential of a novel personalised and modified chimeric antigen receptor (CAR)-natural killer (NK) cell therapy combined with an innovative immune-priming agent. More specifically, we will first modify NK cells using the revolutionary CRISPR-Cas9 technology to make them insensitive to transforming growth factor beta-mediated immunosuppression in the tumour microenvironment. Next, these ameliorated NK cells will be modified to target both the tumour and the surrounding tumour microenvironment using different CAR constructs. Additionally, to invigorate our CAR-NK cell therapy, we will combine this with an immunostimulatory agent. This not only has the capacity to broadly activate the immune system but can also induce a greater attraction of our CAR-NK cells into the tumour to make our CAR-NK cell therapy more efficient. Hence, supported by our encouraging preliminary data, we are convinced that this project has great potential to finally overcome the crucial hurdles that block the advancement of treatment options for PDAC patients.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Pauwels Patrick

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Breast cancer (BC) and cervical cancer (BHK) patients, especially those with advanced disease, are in urgent need of new agents that improve survival and quality of life. One promising strategy is immunotherapy, but the cancer has developed mechanisms that circumvent its effects and benefit only a minority of patients. Recently, the RANK(L) signaling pathway is considered a significant mechanism, as it allows many cancers - including BK and BHK - to disrupt the communication of the immune cells and thus undermine the immune response. Supported by our initial results, we strongly believe that blocking this signal can override the immune system and improve susceptibility to immunotherapy. We therefore seek to reveal the most appropriate anti-RANK(L) immunotherapy to elicit an optimal anti-tumor immune response. Building on the results of our clinical studies, additional laboratory testing will allow us to identify that one, superior combination strategy, which we will further optimize in mouse models. Finally, this project will validate a novel imaging technique to select patients who will benefit from this therapy in order to minimize treatment and financial burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Lardon Filip
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with five-year survival rates of 2-9% and is predicted to become the third leading cause of cancer death in the EU by 2025. PDAC tumors show hypovascularity and vascular compression, causing chemoresistance, resulting from desmoplasia by pancreatic stellate cells (PSCs). Evidence has shown that a pro-angiogenic approach for PDAC increases drug delivery and efficacy, reducing tumor growth and metastasis. Cold atmospheric plasma (CAP) treatment is a novel and safe technology known to induce angiogenesis at low treatment doses. The objective and novelty of my project is to use mild CAP treatment to enhance the delivery and effect of chemotherapeutic drugs by inducing angiogenesis for a synergistic anti-cancer effect. The kINPen® plasma jet will be used to determine optimal CAP treatment conditions. Spheroid co-cultures of pancreatic cancer cells, PSCs and endothelial cells will be investigated. Gemcitabine will be used as chemotherapeutic drug and administration to 3D spheroids will be performed with the novel OrganoPlate® Graft, which allows vascularization of 3D in vitro models and increases the predictive power of in vitro work. Clinical efficacy will be evaluated by combining distal pancreatectomy with intra-operative CAP treatment and adjuvant chemotherapy in an orthotopic mouse model. This project will lead to a novel combinational treatment strategy for PDAC patients that can have partial or full resection.

Researcher(s)

• Promoter: Bogaerts Annemie
• Co-promoter: Privat Maldonado Angela
• Co-promoter: Smits Evelien
• Fellow: Verloy Ruben

Research team(s)

• Plasma Lab for Applications in Sustainability and Medicine - Antwerp (PLASMANT)

Project website

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with mesothelioma remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of only 5%. The current first-line chemotherapy, a combination of cisplatin and pemetrexed, only increases the overall survival by a few months. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are urgently needed in order to improve the prognosis and prolong the survival of mesothelioma patients. Smart combination strategies might improve anti-tumour response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. In this research project tumour-induced immunosuppression will be tackled via two different pathways: PD-L1 immune checkpoint blockade will be used to reactivate silenced anti-tumour immune responses while blockade of the VEGF/VEGFR signalling pathway will be used to target the tumour vasculature in order to reduce angiogenesis, thereby reducing tumour growth. In addition, we plan to assess the positive impact that exercise may have on this combination strategy. Both immune checkpoint blockade and targeted anti-angiogenic treatments have been shown to improve survival in various cancer types. In addition, in vivo work and beneficial immunomodulatory effects suggest the potential of exercise as a non-invasive intervention to increase tumour sensitivity and to potentially synergise with immunotherapies. Therefore, we hypothesize that these treatments will enhance each other's efficacy and will effectively slow tumour growth. Furthermore, we will be the first to investigate the effect of exercise as a co-therapy with immune checkpoint blockade and anti-VEGF. Our data will demonstrate whether exercise as a co-therapy might be beneficial for tolerance and efficacy of our selected combination strategy. Our preclinical study is necessary to investigate a possible synergy of this novel treatment strategy combining immune checkpoint blockade, an anti-angiogenic compound, and exercise. The aim of this project is to meet the urgent need for a new treatment strategy improving both overall survival and quality of life of mesothelioma patients. Since the treatment methods described in this project have already been approved for use in cancer patients, our data can be easily translated into a clinical study.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Marcq Elly
• Fellow: Rovers Sophie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Both targeted and immunotherapies are the key to precision medicine for the treatment of cancer patients. Deregulated signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumourigenesis of multiple cancer types. Furthermore, it is well established that immune checkpoints are crucial for the tumour cell's escape from the immune system. The presence of drug resistance and/or immune evasion is a major obstacle to progress in the field. In our project, we will concentrate specifically on head and neck squamous cell carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Centre for Oncological Research (CORE) Antwerp. To date, there is still an urgent need to enhance the response to cetuximab treatment in recurrent/metastatic (R/M) HNSCC. Over the last years, cetuximab-related resistance mechanisms have been extensively studied at CORE. Based on our results and reports in literature, we hypothesize that inhibiting oncogenic bypass pathways responsible for cetuximab resistance, by a novel treatment strategy can lead to elimination of HNSCC cells that are resistant to treatment with cetuximab alone. In the proposed project, we will investigate the potency of a novel triple combination strategy in order to enhance the response to cetuximab therapy in HNSCC patients. To achieve this, cetuximab will be combined with buparlisib, a selective PI3K inhibitor, and an immune checkpoint inhibitor. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. Furthermore, the nature of our project is translational, as from the beginning, we will use patient-derived HNSCC tumour organoids to validate our results from cell line experiments. These patient-derived tumour organoids are a very innovative and reliable model to identify effective treatment strategies and can actually be considered as a 'patient in the lab'. We are convinced that precision medicine using combinations of targeted therapies with immunotherapy may achieve the much-needed progress in HNSCC treatment. As reported in literature, both cetuximab and buparlisib treatment are able to promote anti-tumour immune response. Therefore, in the first work package, we will characterize the anti-tumour activity and immunomodulating effects of cetuximab in combination with buparlisib in HNSCC cell lines and patient-derived HNSCC organoids. Secondly, we will investigate the immunomodulating effects of cetuximab in combination with buparlisib on immune cells. In parallel, the effect of this combination treatment on the immune checkpoint profile will be assessed. Finally, the novel triple combination therapy consisting of cetuximab, buparlisib and an immune checkpoint inhibitor will be investigated in a humanized, PBMC engrafted HNSCC mouse model. This preclinical work will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the novel triple combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel triple combination strategy, we are confident that the data generated in this project will provide insight into how therapeutic response to cetuximab treatment can be optimized, thus favouring the setup of a successful clinical trial with the newly identified triple combination therapy.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Prenen Hans
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the 6th most common cancer worldwide, and advanced HNSCC patients often experience relapse or metastasis (R/M HNSCC) resulting in dismal prognoses. These patients receive immunotherapy (ICI) alone or in combination with platinum-based chemotherapeutics (PLAT) as first-line treatment. While these combination treatments have some clinical benefit, they are limited by low response rates and severe side effects in already weakened patients. To address this, I will investigate a novel combination strategy with non-thermal plasma (NTP). NTP, an ionised gas, is a localised therapy that induces immunogenic cancer cell death (ICD), which can activate the patient's anti-cancer immunity. To date, no adverse side effects have been reported with the clinical use of NTP. Therefore, we hypothesize that combining NTP with PLAT/ICI will be well-tolerated and improve clinical efficacy in R/M HNSCC. In this project, I will perform 3D in vitro experiments on cell lines and primary patient material, and two mouse models will be used to validate the safety and clinical efficacy of this combination strategy. The successful completion of my project will help integrate NTP into current first-line therapies of R/M HNSCC as a new combination strategy to improve treatment efficacy and quality of life for those patients. This study will also be a stepping stone towards a broader implementation of NTP technology in other cancer types.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Bogaerts Annemie
• Co-promoter: Laukens Kris
• Co-promoter: Lin Abraham
• Fellow: Verswyvel Hanne

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic cancer is one of the most lethal cancer types worldwide, with barely a quarter of the patients still alive one year after diagnosis and a 5-year overall survival below 10%. This dismal outcome is mainly due to its high resistance to all current therapies. Therefore, innovative and effective treatment options are urgently needed for these patients. The tumor microenvironment is stated as the major confounding factor involved in therapy failure. This tumor microenvironment acts as a dense fibrotic shield around the pancreatic cancer cells and additionally creates an immune suppressive environment. Therefore, combination therapies that target both cancer cells and modulate this immune suppressive tumor microenvironment are the next-generation strategies. Hence, in this project I will first modulate the fibrotic shield by using ormeloxifene. This compound is included in the list for drug repurposing in oncology, underlining the fastest and most cost-effective way towards clinical application. Subsequently, I will reinforce the patient's own immune system to eliminate pancreatic cancer cells by exploiting next-generation inhibitory immune checkpoints. With this rationally designed combination, I aim to provide a solid, scientific rationale to initiate a novel clinical trial for pancreatic cancer patients who are in dire need for new treatments options.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc
• Co-promoter: Roeyen Geert
• Fellow: Quatannens Delphine

Research team(s)

• Center for Oncological Research (CORE)

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

The research activities of the consortium IPPON (Integrated Personalized & Precision Oncology Network) are at the forefront of integrated personalized cancer medicine, with emphasis on 1) developing novel and more effective therapeutic strategies; 2) an improved detection and understanding of mechanisms driving therapeutic resistance; and 3) identifying and validating biomarkers for early detection and personalized therapy, in different cancers in need for improved therapeutic outcomes. In this way, we aim to deliver the right treatment to the right cancer patient at the right time. Novel and emerging anticancer strategies that we investigate include - but are not limited to - locoregional perfusion, targeted therapy, immunotherapy, cold atmospheric plasma therapy as well as novel combination therapies. We are convinced that the interdisciplinary collaboration between basic, translational and clinical researchers, catalyzed through this consortium, will enable us to tackle burning research questions and clinical unmet needs to advance the field of personalized cancer medicine. The members of our consortium bring together unrivaled access to biobank patient samples and to a dedicated clinical phase I/II oncological unit with a unique and complementary set of methods and skills covering the entire spectrum of molecular techniques, 2D and 3D cellular assays (in vitro and ex vivo), small- and large animal studies and clinical studies. IPPON gathers experts with an excellent research track record in fundamental, translational and clinical oncology; surgical techniques; targeted therapy; immunotherapy; (epi)genomics; (epi)transcriptomics; proteomics; imaging; liquid biopsies; pathology and clinical studies.

Researcher(s)

• Promoter: Peeters Marc
• Co-promoter: Dewilde Sylvia
• Co-promoter: Hendriks Jeroen
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Smits Evelien
• Co-promoter: Van Dam Peter
• Co-promoter: Vanden Berghe Wim
• Co-promoter: Van den Wyngaert Tim

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is a fatal cancer that is in most patients causally associated with asbestos exposure. Due to its aggressive nature and despite the effectiveness of conventional anti-cancer treatment, the prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5- year survival rate of only 5%. In the last decade, no improvement of survival has been achieved in this disease. Therefore, new therapeutic strategies are needed in order to prolong survival of MPM patients. Smart combination strategies might improve the anti-tumor response by interfering with different hallmarks of cancer and multiple immune escape mechanisms. In this research project tumor-induced immunosuppression will be tackled via two different pathways: immune checkpoint blockade will be used to reactivate silenced anti-tumor immune responses while blockade of the VEGF/VEGFR signaling pathway will be used to target the tumor vasculature in order to reduce angiogenesis thereby reducing tumor growth. In addition, we are keen to assess the positive impact that exercise may have on these combination strategies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: van Meerbeeck Jan

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumour, however it remains a rare disease (incidence: 3.20/100,000). Tumour progression is fast and recurrence inevitable. The added value of the current standard of care (SOC: surgical resection, radiation and chemotherapy) is only limited, leading to a median survival of less than 15 months and a five-year survival of less than 5%. In addition, undesired side effects impact on the quality of life. Hence, new effective treatment modalities represent a highly unmet need. While scientific advances have generated clinical breakthroughs in other cancer types, this has remained a standstill in GBM for nearly 15 years. Immunotherapy has generated remarkable clinical success in the past decade, in particular with immune checkpoint blockade (ICB). Recent preclinical evidence has suggested that combination therapy can render GBM sensitive to ICB. In this project, we will develop an immunometabolic therapy in murine GBM models in vivo as innovative treatment option. We hypothesize that our combination strategy will ameliorate clinical outcome while improving quality of life.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Specenier Pol

Research team(s)

• Center for Oncological Research (CORE)

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

This project represents a research project 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: Smits Evelien
• Fellow: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

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: Lardon Filip
• Promoter: Peeters Marc
• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) and pancreatic cancer (PDAC) are two of the most common and lethal malignancies worldwide. Survival outcomes for the majority of these patients remain very poor due to an advanced stage at diagnosis and their rapid progressive nature. The first-line treatment of advanced NSCLC in most patients still consists of conventional chemotherapy to achieve tumor response or stable disease. Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine/nab-paclitaxel or FOLFIRINOX which have only modest improvements in survival due to chemoresistance in most patients. Therefore, there is a high unmet need for novel and more effective treatment approaches for both cancer types. This dire need for new therapeutic options encouraged me to provide the fastest way towards clinical application. Therefore, we used the orally available, lipophilic, organogold compound Auranofin (AF), which is included in the list of the ReDo (Repurposing Drugs in Oncology) project established by the Belgian non-profit Anticancer fund. I was the first to show the therapeutic anticancer potential of AF in mutant p53 NSCLC and PDAC cancer cell lines in which it triggered distinct molecular cell death mechanisms (apoptosis, ferroptosis and immunogenic cell death) by inhibiting the thioredoxin and glutathione redox systems and inducing oxidative stress (Freire Boullosa et al., 2021). Furthermore, I showed the relevance of targeting thioredoxin reductase in NSCLC patients, since it is overexpressed in NSCLC cells compared to the surrounding tissue. Despite these promising results as a single agent, I am convinced that the true power of AF lies within rationally designed drug combination strategies. This is supported by my recent work on the highly synergistic combination of AF and the PARP-1 inhibitor Olaparib which is effective in in vitro and in vivo NSCLC and PDAC models (ongoing). In addition, an increasing number of publications highlights the potential of AF in combination with chemotherapeutic agents, mTOR inhibitors, ROS inducers, etc. which resulted in several Phase I and II clinical trials. Therefore, the goal of this study is to perform a high-throughput drug combination screening with AF and a literature-based / clinically available drug panel based on standard of care regimens and inhibitors of KRAS effector pathways, in a set of patient-derived NSCLC and PDAC 3D organoids using our in-house developed drug screening platform Orbits. This allows us to study for the first time which AF drug combination strategies are the most promising and which baseline patient characteristics are related to therapy response using the most clinically relevant in vitro model available to date based on the genomic and transcriptomic characterization of these organoid lines. Overall, drug repurposing of the off-patent drug AF will contribute to a positive impact on patient outcome and quality of life, to a faster clinical implementation and to a lower healthcare cost.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer immunotherapy strategies leave room for improvement. Given that a 'one-size-fits-all' approach is not the solution due to tumor heterogeneity, personalized therapy is the way forward. It is my mission to overcome hard-to-treat solid tumors and to push boundaries in achieving effective personalized immunotherapies. To accomplish this, the immunosuppressive nature of the tumor microenvironment needs to be overcome, allowing to significantly reduce its hampering effect on the activation and the infiltration of immune cells in tumors. My team recently demonstrated the power of certain activated immune cells to kill both cancer cells and cells of the tumor microenvironment that contribute to immunosuppression. With a view to further enhance antitumor effects, me and my team will unravel different inhibitory mechanisms that hamper antitumor immune cell responses and use these new insights to develop effective and personalized therapies that combine direct activation of immune cells with inhibition of immunosuppression. In the current 2-year project, we will gather novel tumor immunology data on 1) characterization of the tumor microenvironment, 2) interactions between tumor cells and immune cells, 3) relevant targeted treatment strategies and 4) biomarker identification; as important proofs-of-concept to further strengthen my European and consortium project applications in the near future.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Bogaerts Annemie

Research team(s)

• Center for Oncological Research (CORE)

Project website

Project type(s)

• Research Project

Abstract

Cancer therapy has been rapidly transforming in part due to progress in seemingly unrelated fields. This has led to the development of profound tools for studying cancer pathways and innovative therapies. Non-thermal plasma (NTP) is a novel treatment that has been emerging for cancer immunotherapy. Bioinformatics is another field experiencing rapid growth, as the ability to collect and process large amounts of 'omics' data has become increasingly accessible. In the context of oncology, this has led to success in elucidating therapy-induced pathways and therapy target discovery. Therefore, in my project, I will use a combination of experimental and bioinformatics approaches to study fundamental effects of NTP on cancerous cells: 1) mechanisms driving cell sensitivity and 2) immunological changes to be exploited for combination therapy. In vitro experiments will be performed to categorize cells into sensitivity groups based on NTP-induced cell death; cellular redox and death modalities will also be studied. Transcriptome analysis and bioinformatics techniques will be used to uncover the activated pathways. Signature gene sets from transcriptome data will be studied to obtain a more comprehensive picture of the immunologic changes in NTP-treated cells. All in silico results will be validated experimentally. Success of this project will benefit multiple science fields and open new lines of research while providing insight into underlying mechanisms of NTP-induced cancer response.

Researcher(s)

• Promoter: Bogaerts Annemie
• Co-promoter: Laukens Kris
• Co-promoter: Smits Evelien
• Fellow: Lin Abraham

Research team(s)

• Plasma Lab for Applications in Sustainability and Medicine - Antwerp (PLASMANT)

Project website

Project type(s)

• Research Project

Abstract

Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. In our search for new anticancer therapies, we discovered that Auranofin, an old drug currently used for rheumatoid arthritis, is highly effective against mutant p53 expressing cancer cells. P53 is the most frequently mutated gene in lung cancer and is often associated with an unfavorable therapeutic outcome. Auranofin is a selective inhibitor of the antioxidant thioredoxin reductase. Previous studies have shown that Auranofin dependent inhibition of this antioxidant blocks several pro-tumorigenic pathways. Recent findings have shown that these pathways are also involved in attracting immunosuppressive cells to the tumor microenvironment and in hiding cancer cells from immune cells. To date, little is known about the underlying mechanisms by which AF induces cancer cell death and if Auranofin can modulate the immune suppressive tumor microenvironment. In this strategic basic research project, we recently discovered that Auranofin induces different types of immunogenic cell death pathways, including the type of cellular 'rust' ferroptosis, which can stimulate the patient's immune cells to efficiently eliminate lung cancer cells. In addition, we will study the in vivo effect of Auranofin on different types of immune cells inside the tumor and peripheral blood to determine if Auranofin is a potential candidate for combination strategies with immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Acute myeloid leukemia (AML) is a hematological cancer that arises and spreads from the bone marrow. It has a very dismal prognosis, characterized by a high relapse rate, despite initial complete molecular remission. Residual leukemic stem cells (LSC) are believed to be to origin of this relapse. LSC reside in a tumoral bone marrow that features a heightened state of hypoxia. Immunotherapeutic strategies are on the rise and are promising approaches to go hunt-and-destroy LSC. However, they will have to overcome the hypoxic burden in the leukemic bone marrow. Indeed, hypoxia is nowadays recognized as a barrier for immunotherapy. In this project, we will focus on natural killer (NK) cells as a born killer with great potential as adoptive cell product. While cytokines and chimeric antigen receptors (CAR) have improved the cytotoxic potency and targetability of NK cell products, their effectiveness at the tumor site is incapacitated by hypoxia. To address this conundrum, we will investigate several approaches to metabolically sustain their killing capacity in hypoxia in order to elicit potent elimination of both LSC and differentiated AML cells in the leukemic bone marrow. This will open up opportunities to develop next-generation CAR NK cells as an available off-the-shelf product for the treatment of AML patients.

Researcher(s)

• Promoter: De Waele Jorrit
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite the many scientific successes in ameliorating the outcome for cancer patients, cancer still remains the second leading cause of death worldwide, with about 1 in 6 deaths due to cancer. Therefore, we still have a long and difficult road ahead in finding new and improved cancer therapeutics. A major gamechanger in the treatment of cancer patients is the breakthrough of immunotherapy. Especially the introduction of immune checkpoint inhibitors resulted in significant increased overall response rates for several cancer types. However, despite their success, several disadvantages and hurdles to further improve the outcome of cancer patients are still present. Therefore, other strategies of cancer immunotherapy need to be explored to overcome or circumvent these drawbacks. Two promising approaches are currently in the scoop of cancer immunotherapy research, being (i) the use of natural killer cells to fight tumour cells and (ii) turning cold immunogenic tumours into hot immunogenic tumours. We have shown in our lab that natural killer cells can play a significant role in a cold immunogenic tumour like pancreatic ductal adenocarcinoma (PDAC). More specifically, after stimulation with interleukin(IL)-15, natural killer cells are able to not only kill the tumour cells but also the surrounding immunosuppressive stromal cells of the tumour microenvironment. Furthermore, we also demonstrated that the anti-tumour potential of IL-15 is significantly enhanced combined with an immunotherapeutic agent that works on antigen presenting cells. With the results of this project, we aim to initiate a first-in-human clinical trial with our combination immunotherapy. Patients suffering from various tumour types, including some which are not responding to standard chemo-/radiotherapy or current immune checkpoint inhibitors, could potentially have a better treatment outcome in the future.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Natural killer (NK) cells are potent cytotoxic cells from the hematopoietic system, playing an important role in the control of infection and malignancy. NK cells often operate under harsh conditions, such as in deprived oxygen or hypoxia. Hypoxia stabilizes its primary regulators hypoxia-inducible factors (HIF), more specifically HIF-1? and HIF-2?. While hypoxia reduces NK cell-mediated cytotoxicity, data on other NK cell features is conflicting. In addition, the role of HIF in NK cells has been neglected, as only one mouse study demonstrated that HIF-1? ablation in NK cells indirectly reduces tumor load via angiogenic rather than cytotoxic effects. However, murine NK cells show quite some disparities to human NK cells. In addition to hypoxia, also stimuli such as cytokines can stabilize HIF. Hence, HIF could play a pivotal role in NK cells. Therefore, this project aims to gain fundamental insights in the role and regulation of HIF in human NK cells via combining omics with functional assays. First, we will unravel the effect of hypoxia on (stimulated) NK cells. Next, we will dissect the divergent roles of HIF-1? and HIF-2? in the functioning of NK cells in response to hypoxic and stimulatory conditions. HIF isoform-specific knockout NK cells will be created using CRISPR-Cas9. Finally, we will elucidate how HIF isoforms regulate their effects in NK cells. The obtained knowledge could prove extremely valuable in rational guidance of rising novel NK-cell based immunotherapies.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic cancer (PDAC) is the 3th leading cause of cancer related death in the western world and the incidence is still rising. Due to its rapidly progressive nature and lack of early symptoms, 80-90% of the patients present itself late with advanced or metastatic disease. This results in the worst 5-year survival of all cancers (7%). Current treatment options for PDAC are limited since only 10-20% of the patients is eligible for curative surgical resection. The remaining patient population is treated with gemcitabine which has only modest improvements in survival due to chemoresistance in the majority of patients. The promising advantages that have been made in several cancer types are in great contrast with the scarce therapeutic improvements in PDAC. The tumour microenvironment (TME) is believed to be a major confounding factor involved in failure of conventional therapies, as well as in targeted and immune therapy. A hallmark of this microenvironment in PDAC is the strong desmoplastic reaction, orchestrated by the pancreatic stellate cells (PSC), which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC). This stroma, which can cover more than 50% of the tumour, consists of extracellular matrix, activated PSC and a variety of immune cells such as macrophages, T-lymphocytes, dendritic cells and natural killer cells. By acting as a mechanical and functional shield to the tumour, it plays a central role in the development, progression and invasion of PDAC and also creates an immunosuppressive TME by secretion of immunosuppressive factors. Therefore, we will attack PDAC on both fronts being the cancer cells and its surrounding stromal shield. To achieve this, we will investigate a novel, highly potent combination immunotherapy for PDAC, consisting of both immune stimulatory as well as anti-immune suppressive agents.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In this project we aim to develop a novel combination therapy to treat cancer that combines induction of oxidative stress with immune checkpoint inhibition. By this project, we will obtain insight in the underlying mechanisms of ionized gas for cancer treatment by doing in vitro and in vivo experiments. We will investigate the effects of both direct and indirect treatment on pancreatic cancer and melanoma cells, in terms of: 1) induction of reactive species, 2) selectivity towards cancer cells versus normal cells, 3) effect of hypoxia; and 4) immunogenicity. Next, we will test the therapeutic effect of the combination of oxidative stress with immune checkpoint inhibition.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Quatannens Delphine

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Colorectal cancer (CRC) retains its position as one of the most prevalent types of cancer with around 700,000 deaths per year worldwide. Treatments focused on altering the immune system have recently paved their way into oncology with clinical achievements seen in a broad spectrum of solid tumors. However, signals of activity in CRC are largely involving microsatellite instable tumors, leaving a great need for effective immunotherapy in the majority of patients. The biologica! complexity of the tumor microenvironment seems to be an obstacle for cancer immunotherapy, suggesting that a strategy to solely targeting tumor cells is inadequate to overwhelm the aggressively growing tumor in CRC. Cancer-associated fibroblasts (CAFs) represent the dominant constituents of the tumor stroma and play a critica! role in the proliferative and invasive behavior of CRC. Additionally, CAFs provide a physical barrier for the efficient delivery of systemic therapy to the tumor making it an attractive target to combine with conventional treatment. Clinically addressing CAFs has been challenging due to its heterogeneous nature with both cancer-promoting and cancer-restraining features. We have recently identified a phenotypically distinct subset of CAFs in invasive CRC specimens, marked by the expression of CD70, and associated with poor prognosis of the patient. Moreover, CD70-positive CAFs proved to stimulate tumor invasion and to promote immune escape by the accumulation of immune suppressive regulatory T-cells. lnterestingly, CD70 is totally absent from normal epithelial tissue making it a safe target to eradicate the tumor-promoting CAFs. Based on our preliminary data, we hypothesize that targeting CD70-positive CAFs in CRC has a potential triple mode of action by enhancing anti-tumor immunity, eradicating a permissive niche for tumor invasion and increasing the efficacy of first-line chemotherapeutics. The primary objective of the proposed project is to find the ideal approach to deplete CD70-positive CAFs. The second objective is to design a combination strategy of CD70-targeted therapy with a first-line chemotherapeutic agent that elicits a potent anti-tumor immune response. The third objective is to identify potential bloodbased biomarkers for diagnosis and to monitor treatment response. Experiments will be performed in vitro under normoxic and hypoxic conditions and in vivo in an orthotopic syngeneic mouse model to identify the ideal timing and dosing of our combination strategy. This translational research project wil! lead to the launch of a phase 1/11 clinical trial in patients with advanced CRC with a grim prognosis of only 12 to 14 months. Since we have also found CD70 expression in the desmoplastic stroma of pancreatic cancer, this study will also pave the way to application in one of the most therapeutically resistant maliçinancies.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Jacobs Julie
• Co-promoter: Lardon Filip
• Co-promoter: Peeters Marc
• Co-promoter: Rolfo Christian
• Co-promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Both targeted therapies and immunotherapies are now at the forefront of personalized cancer medicine. Aberrant signalling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumorigenesis of multiple cancer types, making it a compelling drug target. In addition, it is well established that natural killer (NK) cells possess natural anti-tumour activity and can mediate antibody dependent cellular cytotoxicity (ADCC) upon binding with monoclonal antibodies, such as the EGFR inhibitor cetuximab. However, the presence of drug resistance and/or immune evasion is a major obstacle to progress in this field. In our project, we will concentrate specifically on head and neck squamous carcinoma (HNSCC), a highly relevant tumour type with poor prognosis that is intensively studied at the Center for Oncological Research (CORE) Antwerp. In this research project, we hypothesize that increasing the NK cell activity by cetuximab in combination with targeting NK cell immune checkpoint molecules can synergistically generate immune mediated elimination of HNSCC cells that are resistant to treatment with cetuximab alone. Importantly, we will investigate the role of human papilloma virus (HPV) in this response, as HPV positive HNSCC patients represent a biologically distinct group. By characterizing NK cell functionality and, by extension, the whole immune checkpoint profile in HNSCC, we aim to rationally design new combination strategies to overcome cetuximab resistance, with the ultimate goal to improve the prognosis and life quality of HNSCC patients. Hereby, we will focus on HPV status and the hypoxic microenvironment as important mediators of treatment response. Therefore, the nature of our project is translational, as from the beginning, the link with clinical data is considered to be imperative before moving on to further preclinical investigation of the identified combination strategies. Successful combinations will be validated in animal studies, which will ultimately guide the start-up of a clinical trial to demonstrate feasibility of the most promising combination therapy to treat HNSCC patients. Given the extensive preclinical (both in vitro and in vivo) and translational work packages to optimise the novel combination strategy, we are confident that the data generated in this project will favour the setup of a successful clinical trial with the newly identified combination regimen.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Peeters Marc
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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.

Researcher(s)

• Promoter: Laukens Kris
• Co-promoter: Meysman Pieter
• Co-promoter: Smits Evelien
• Co-promoter: Van Tendeloo Vigor
• Fellow: Gielis Sofie

Research team(s)

• ADReM Data Lab (ADReM)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive cancer that is causally associated with previous, mostly professional, asbestos exposure in most afflicted patients. Although preventive measures to limit asbestos use and exposure have been around for several decades, the incidence of MPM is still expected to increase over the next decade due to the long latency between asbestos exposure and MPM development. The prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and a 5-year survival rate of less than 5%, due to its aggressive nature and the limited effectiveness of any conventional anti-cancer treatment (i.e. chemotherapy, surgery and radiotherapy). The new chemotherapy regimens consisting of a combination of a platinum compound and the folate antimetabolites pemetrexed or raltitrexed have a significant but limited impact on overall survival in MPM. Therefore, new therapeutic strategies are needed to complement the limited armamentarium against MPM. The observation that the immune system can recognize and eliminate tumors is the impetus of the fast-growing research domain of cancer immunotherapy. With the discovery of immune checkpoints, immunotherapy of cancer has entered a new and exciting phase. Clinical studies in a.o. melanoma, renal cell cancer and lung cancer have shown that anti-PD-1 immunotherapy has durable clinical activity, even after treatment cessation, resulting in approval. Also anti-PD-L1 immunotherapy has been approved for treatment of different cancers. PD-1 and PD-L1 expression data in MPM of us and others laid the basis to evaluate their suitability as immunotherapeutic targets also in MPM. Two clinical trials, investigating PD-1 or PD-L1 inhibition in mesothelioma (KEYNOTE-28 and JAVELIN trial, respectively), have already shown promising results with room for improvement. Two other immune checkpoints, being lymphocyte activation gene-3 (LAG-3) and T-cell mucin immunoglobulin-3 (TIM-3), recently gained more interest since they have been described to be associated with T-cell tolerance and exhausted T cells that are infiltrating the tumor micro-environment. Our data on TIM-3 and LAG-3 expression in MPM effusions and on TIM-3 in MPM tissue samples identify both as promising new targets in MPM. Combined targeting of PD-1/PD-L1 with TIM-3 or LAG-3 was highly effective in controlling tumor growth in vivo in different other solid tumor models, providing a rationale to investigate combined blockade also in MPM. Smart combination strategies might improve the antitumor response by interfering with multiple immune escape mechanisms.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Marcq Elly

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Non-small cell lung cancer (NSCLC) remains the leading cause of cancer mortality worldwide and a marginally improving 5-year overall survival rate which remains below 20%. Successful therapeutic advances have emerged, but these treatment options are limited to only a small subset of NSCLC patients. Therefore, new treatment strategies are needed that will result in durable responses for the majority of NSCLC patients. In this regard, combining an immune modulatory chemotherapeutic agent with immunotherapy would be a suitable and promising approach. On the one hand, it has been shown that certain chemotherapeutics can induce immunogenic cell death, thereby releasing neoantigens and enabling tumor-specific cytotoxic T cell responses. On the other hand, CD70 has emerged as a promising target to be blocked in various hematological and solid malignancies. Its overexpression on tumor cells is associated with immune suppression in the tumor microenvironment. CD70 overexpression on NSCLC cells was detected by us in a subset of patients (16%). More importantly, preliminary findings from our group demonstrated the ability of certain chemotherapeutics to induce CD70 overexpression on NSCLC cells, which broadens the therapeutic window of anti-CD70 immunotherapy. Built on these preliminary findings, the primary aim of this study is to identify the ideal chemotherapeutic agent to combine with anti-CD70 immunotherapy by thoroughly evaluating several chemotherapeutics for their capacity to induce immunogenic cell death and stimulate CD70 overexpression on NSCLC cells. The second aim is to investigate the anti-tumor capacity of this treatment strategy together with the recently approved immune checkpoint inhibitor anti-programmed death (PD)-1, in order to develop an innovative approach that tackles the immunosuppressive factors of the tumor from different angles. Experiments will be performed in vitro in normoxic and hypoxic conditions and in vivo in a syngeneic mouse model. This project has the exciting potential to unravel a novel combination strategy for NSCLC patients that enables specific targeting of the tumor cells and realizes durable responses by stimulating the anti-tumor immune response. In addition, these study results might also pave the way for improved treatment options in other tumor types.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Jacobs Julie
• Co-promoter: Smits Evelien
• Fellow: Flieswasser Tal

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cold atmospheric plasma (CAP) is gaining interest for cancer treatment, although the application is still in its early stages. Besides direct CAP treatment of cancer cells, plasma can also be used to treat liquids, which appear to have similar anti-cancer effects as the plasma itself. These plasmatreated liquids (PTL) are very promising for cancer treatment, as they can be more generally used, e.g. they might be directly injected into tissue of patients. However, the selectivity of PTL treatment towards cancer cells, leaving normal cells undamaged, is only scarcely explored. This is exactly the focus of this project. We will try to define which cancer cell types are more (or less) sensitive towards PTL treatment and how selectivity towards cancer cells can be promoted. For this purpose, we will link the chemical composition of the PTL (reactive oxygen, nitrogen and chlorine species) with the selectivity in cancer vs. normal cell cytotoxicity, to know which species promote this selectivity (WP1). In parallel, we will develop a 0D and 2D computational model to simulate the plasma-liquid interactions (WP2+3). With the knowledge obtained in WP1, we can use the models to elucidate which plasma treatment conditions enhance the selectivity. Then, we will apply these conditions in the patient cell experiments to optimize the selectivity (WP4). Finally, we will also strive to unravel the underlying mechanisms of this selectivity in the cell experiments (WP4).

Researcher(s)

• Promoter: Bogaerts Annemie
• Co-promoter: Smits Evelien
• Fellow: Van Boxem Wilma

Research team(s)

• Plasma Lab for Applications in Sustainability and Medicine - Antwerp (PLASMANT)

Project website

Project type(s)

• Research Project

Abstract

Both targeted therapies and immunotherapies are now at the forefront of personalized cancer medicine. Aberrant signaling of the epidermal growth factor receptor (EGFR) plays an integral role in the tumorigenesis of head and neck squamous cell carcinoma (HNSCC), making it a compelling drug target. In addition, it is well established that natural killer (NK) cells possess natural antitumor activity and can mediate antibody dependent cellular cytotoxicity (ADCC) upon binding with monoclonal antibodies, such as the EGFR inhibitor cetuximab. However, the presence of drug resistance and/or immune evasion is a major obstacle to progress in this field. In this research project, we hypothesize that increasing the NK cell activity by cetuximab in combination with targeting of NK cell immune checkpoint molecules can synergistically generate an immune mediated elimination of HNSCC cells that are resistant to treatment with cetuximab alone. Importantly, we will investigate the role of human papilloma virus (HPV), as HPV positive HNSCC patients represent a biologically distinct group. By characterizing NK cell functionality and, by extension, the whole immune checkpoint profile in HNSCC, we aim to rationally design new combination strategies to overcome cetuximab resistance, with the ultimate goal to improve the prognosis and life quality of HNSCC patients. Hereby, we will focus on HPV status and the hypoxic microenvironment as important mediators of treatment response.

Researcher(s)

• Promoter: Lardon Filip
• Co-promoter: Smits Evelien
• Co-promoter: Wouters An
• Fellow: Baysal Hasan

Research team(s)

Project type(s)

• Research Project

Abstract

Cancer is still a major healthcare issue and many conventional therapies overlook the role of the immune system in the resolution of this disease. Non-equilibrium plasma is emerging as a novel cancer treatment. Promising results showed that plasma can kill cancerous cells and stimulate immune cells, but experiments have largely been in vitro. To address this, we will perform in vivo mouse experiments to validate therapeutic efficacy of plasma and assess immune responses required to eliminate cancer. While treatment may be efficacious, the underlying mechanisms of plasma cancer therapy are not fully understood. When plasma is generated, a complex environment of electric fields, ultraviolet light, charged particles and neutral species is produced. To date, it is unclear which plasma components and reactive species play the major role in cancer therapy. Therefore, we will also delineate the components of plasma that elicit anti-cancer responses. In addition, we will develop a computational model that will predict the behavior of plasma-generated species in liquid, as cells and tissue are treated in the presence of liquid. This will be compared to chemical analysis of plasma-treated liquid for validation and establishment of crucial species for cancer therapy. Altogether, this project will support development of plasma technology for cancer immunotherapy and provide insight into the underlying mechanisms.

Researcher(s)

• Promoter: Bogaerts Annemie
• Co-promoter: Smits Evelien
• Fellow: Lin Abraham

Research team(s)

• Plasma Lab for Applications in Sustainability and Medicine - Antwerp (PLASMANT)

Project website

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 "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)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Smits Evelien
• Fellow: Van Acker Heleen

Research team(s)

• Laboratory for Experimental Hematology (LEH)

Project type(s)

• Research Project

Abstract

Cancer treatment is advancing to personalized precision medicine following the continuous development of new targeted therapies and immunotherapies. Despite several recent breakthroughs, lung cancer remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer is characterized by a 5-year survival rate of less than 20%, which is often the result of resistance mechanisms against current therapies. At the Center for Oncological Research we focused on targeting the tumor suppressor p53 protein to overcome resistance to conventionally used DNA-damaging agents. We showed that therapeutic reactivation of either wild type or mutant p53 greatly increased the cytotoxic response to cisplatin in a synergistic manner. Now we want to further improve these results by involving the immune system in the antitumor effect. Therefore, this study will explore the potential of p53 targeting therapies, as monotherapy or in combination with the DNA-damaging agent cisplatin, to eliminate tumor cells by recruitment and activation of natural killer (NK) cells via the receptor NKG2D. For this, we will study (I) the p53 dependent induction of NKG2D ligand expression and NK cell targeting chemo- and cytokine secretion in a panel of NSCLC cell lines; (II) NK cell-mediated NSCLC tumor cell killing in co-culture experiments; and (III) the potential additional antitumor effect of interleukin 15 as potent NK cell activator. The outcome of this study could result in an innovate therapeutic strategy which combines a DNA-damaging agent with state-of-the-art targeted- and immunotherapy. As such, tumor cells can be targeted more directly and eliminated using the patient's own defense systems.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Deben Christophe
• Fellow: Freire Boullosa Laurie

Research team(s)

Project type(s)

• Research Project

Abstract

Recently, a new approach based on non-thermal plasma (NTP) to treat cancer cells is gaining interest in the medical field. Plasma is an ionized gas. It is a highly reactive mixture, containing electrons, ions, radicals and energetic neutrals, while still operating at room temperature. Precisely this combination of reactive species and low gas temperature makes it suitable for treating biological samples. It is suggested that the killing capacity of plasma is related to the formation of reactive oxygen and nitrogen species (RONS). Moreover, previous research showed that plasma can selectively kill cancer cells over healthy cells, which is an advantage over traditional treatment methods, such as radio- and chemotherapy. Unfortunately, little is known about the actual working mechanism, or selectivity, making it difficult to convince pharmaceutical collaborators to invest in this technique and develop it into a valuable treatment option for cancer. During this research, I will investigate the anti-cancer capacity of NTP, which RONS are responsible, and how NTP alters the DNA damage response (DDR) of cancer cells. The latter is a collection of mechanisms that are activated whenever DNA damage is detected in order to repair it. This is interesting because (a) plasma is shown to induce DNA damage, and (b) it is known that the DDR of cancer cells is already partially compromised, making it a valuable oncological target. I will use a brain tumour, glioblastoma multiforme, as model.

Researcher(s)

• Promoter: Bogaerts Annemie
• Co-promoter: Smits Evelien
• Fellow: Vanuytsel Steven

Research team(s)

• Plasma Lab for Applications in Sustainability and Medicine - Antwerp (PLASMANT)

Project website

Project type(s)

• Research Project

Abstract

Cancer cells are embedded in stroma, the connective tissue framework of solid tumors. The mutual and interdependent interactions between the cancer cells and their microenvironment (TME) are increasingly recognized as effective targets for cancer therapy. The most abundant cells in the TME are the cancer-associated fibroblasts (CAFs). Although it has been shown that CAFs play an important role in the proliferative and invasive behavior of colorectal cancer (CRC), CAFs represent a heterogeneous population with both cancer-promoting and cancer-restraining actions, lacking specific markers to target them. Although absent from normal tissue, various tumor types have shown expression of CD70 on the malignant cells. It has been demonstrated that these CD70-positive tumor cells can suppress the immune system by inducing an accumulation of the immune suppressive regulatory T cells (Tregs). In this study, we will be the first to determine the role of CD70 in CRC, not merely focusing on the tumor cells but also taking the TME into account. Our preliminary data point towards the expression of CD70, not on the tumor cells itself but on the CAFs in CRC. Moreover, our results have shown that the presence of CD70 on the CAFs was associated with poor prognosis of the patient. In this project, we will further investigate the role of CD70-positive CAFs in CRC. Thereby, we will assess the migratory and invasive properties of CD70-positive CAFs and investigate its effect on the tumor cells. In addition, we will determine whether expression of CD70 on CAFs enhances immune suppression by the accumulation of Tregs. These experiments will lead to the completion of a PhD.

Researcher(s)

• Promoter: Pauwels Patrick
• Co-promoter: Smits Evelien
• Fellow: Jacobs Julie

Research team(s)

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

Non-small cell lung cancer (NSCLC) retains its position as the most lethal type of cancer with around 1.3 million deaths per year worldwide and a marginally improving 5-year overall survival rate which remains below 20%, pointing to the need for new therapeutic options. Immunotherapy, in which the patient's immune system is used to selectively eliminate cancer cells, is considered a very promising candidate. Results of the recently approved immunotherapeutic agent nivolumab underscore the potential of immunotherapy in NSCLC, but also leave room for improvement. This study will focus on the CD70-CD27 signaling pathway as an interesting novel target to enhance anti-tumoral immune responses in NSCLC in combination with low doses of chemotherapy. CD70 is a member of the tumor necrosis factor family and its expression is normally restricted to activated T and B cells. Constitutive expression of CD70 by tumor cells can facilitate immune evasion by increasing the amount of suppressive regulatory T cells, inducing T cell apoptosis and skewing T cells towards T cell exhaustion. Previously, we have detected constitutive overexpression of CD70 in NSCLC tumor specimens, also in patients that lack other targeted treatment options. This CD70 expression can be exploited by CD70-targeting antibody-dependent cellular cytotoxicity (ADCC)-inducing antibodies. Our preliminary data show that the combination of anti-CD70 therapy with low doses of chemotherapy significantly increases cytotoxicity of the drug, compared to single treatment regimens. The main objective of the current project proposal is to rationally design and to preclinically evaluate a combination therapy of chemotherapy with CD70-targeted immunotherapy as a novel treatment option for patients with NSCLC.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Lardon Filip
• Co-promoter: Pauwels Patrick
• Co-promoter: Rolfo Christian
• Co-promoter: Van Schil Paul

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

In this project we will perform a randomized controlled phase II study in which we test a therapeutic cancer vaccine comprising WT1 mRNA-loaded autologous dendritic cells. The primary aim of the study is to investigate the efficacy of the vaccine for AML patients in complete remission at high risk of relapse, both at the level of disease-free survival and overall survival.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor and is characterized by a poor prognosis.The cancer cells reside in a hypoxic environment, which supports tumorigenesis, amongst others via suppression of immunity. A burning question is whether plasma as an ionized gas is able to kill cancer cells in a way that makes the immune system active, also known as 'immunogenic cell death'. In this study, we will investigate whether plasma induces immunogenic cell death in glioblastoma cells and whether it can activate immune cells. The effect of hypoxia will also be investigated. We collect these data to gain more insight into the mechanism of action of plasma as a necessary component to obtain approval of a new therapy and to lay the foundation to examine combination therapies in the next phase of the project.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van Loenhout Jinthe

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Despite major medical advances, acute myeloid leukemia (AML) still has a poor prognosis with a 5-year survival rate of 26%. Therefore, there is a clear need for new effective therapies that can destroy remaining malignant cells, which are not killed after the standard treatment. At present, there is much interest in the use of dendritic cell (DC)-based vaccination, as this cell therapy is capable of mobilizing the patient's own immune system, resulting in the in vivo generation of an anti-tumor response without serious toxicity or side effects. However, clinical effectiveness of DC vaccines need to be further improved. A few years ago, the U.S. National Cancer Institute has named interleukin (IL-)15 as the most promising molecule for translational oncology research and for use in therapeutic cancer vaccines. The aim of this innovative research is the in vitro generation and characterization of IL 15 trans-presenting 'designer' DC with optimized immunostimulatory capacities for the induction of efficient antitumor immune responses in AML. Our hypothesis is that DC loaded with mRNA coding for IL-15 and IL-15 receptor α trans-present IL-15 and are able to induce a strong and effective anti-tumoral immune response by activating the main killer cells of the immune system. To ensure the specificity of the antitumor response, DC will also be loaded with the leukemia-associated Wilms' tumor (WT1) antigen, which is overexpressed in AML patients. Unfortunately, immune checkpoints (e.g. programmed cell death protein (PD-1/PD-L1) interactions) could impede the immunostimulatory effects of our IL 15 trans presenting DC. Therefore, decreasing the expression of the ligands of PD 1 on DC, can result in a more powerful antitumor immune response. Overall, the combination of all these modifications turns our 'designer' DC vaccine into the ideal candidate to activate the antitumor immune system to treat (leukemic) tumor cells.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

Project website

Project type(s)

• Research Project

Abstract

Support for the development of novel combination strategies with immunotherapy to treat solid tumors, as well as to investigate immune escape mechanisms of cancer cells and to characterize the tumor immune microenvironment

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

This research community is focused on gaining a better insight in the relationship between the physicochemical properties of nanomaterials for drug delivery and in vivo imaging on the one hand and their biological behavior with a focus on biodistribution in biological fluids, recording and processing in cells and toxicity on the other hand.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer related death in the western world and incidence is still rising. Due to its rapidly progressive nature and lack of early symptoms, up to 80% of the patients present itself late with advanced or metastatic disease. This results in an extremely poor prognosis and a 5-year survival below 5%. Current treatment options for PDAC are limited since only 10-15% of the patients are eligible for curative surgical resection. The remaining patient population is treated with chemotherapy which has only modest improvements in survival due to chemoresistance in the majority of patients. The tumour microenvironment (TME) is believed to be a major confounding factor involved in failure of different therapeutic strategies. A hallmark of this TME in PDAC is the strong desmoplastic reaction which results in a dense fibrotic/desmoplastic stroma that surrounds the pancreatic cancer cells (PCC). By acting as a mechanical and functional shield around the tumour, it plays a central role in the development, progression and invasion of PDAC and also creates an immunosuppressive TME. In this strategic basic research project, novel combination immunotherapies will be investigated in search for better treatment options for PDAC patients. Both immune stimulation and inhibition of immune suppression will be employed, with a special focus on the TME.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Peeters Marc
• Fellow: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

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)

• Promoter: Van Tendeloo Vigor
• Co-promoter: Smits Evelien
• Fellow: Van Acker Heleen

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

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

Malignant pleural mesothelioma (MPM) is a highly aggressive and fatal cancer that affects the membranes lining the lung and is mostly associated with previous exposure to asbestos. Till today, prognosis of patients diagnosed with MPM remains dismal with a median overall survival of only 9-12 months and currently available treatment methods have only a limited impact on it. Therefore there is an urgent need for new treatment methods. During my PhD project I will investigate the immune checkpoint programmed death-1 (PD-1) and its ligands, PD-L1 and PD-L2, as immunotherapeutic targets in MPM. It is presently unknown if blocking these targets have any effect in MPM but clinical trials in several tumor types have already shown promising results for PD-1 and PD-L1 immunotherapy.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: van Meerbeeck Jan
• Fellow: Marcq Elly

Research team(s)

Project type(s)

• Research Project

Abstract

This innovative basic research project is situated in the development of effective immunotherapeutic strategies for GBM. Elimination of both GSC and differentiated GBM tumor cells by innate immune cells is inhibited by GBM-mediated immune escape and suppression in a hypoxic tumor microenvironment. In the proposed research project, we aim to break this immune escape and suppression of GBM cells and GSC.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

To our knowledge, we will be the first to investigate the immune inhibitory receptor PD-1 and its ligands PD-L1 and PD-L2 as immunotherapeutic targets in human MPM. Until now, there are no data available on the expression of PD-1 and PD-L2 in MPM patients, hampering their evaluation as novel therapeutic targets. This project aims to fill this major knowledge gap and to provide basic insights in the potential therapeutic efficacy of blocking antibodies that target PD-1, PD-L1 and/or PD-L2 in MPM.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

The prognosis of malignant pleural mesothelioma (MPM) patients remains dismal with a median overall survival of only 9-12 months. The immune system plays a critica I role in protection against MPM with preliminary clinical evidence that immunotherapy can lead to MPM contro!. Here, we will be the first to investigate the immune checkpoint programmed-death 1 (PD-1) and its ligands as novel and potentially highly effective immunotherapeutic targets in MPM.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Pauwels Patrick
• Co-promoter: van Meerbeeck Jan

Research team(s)

Project type(s)

• Research Project

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a common gastrointestinal malignancy characterized by rapid progression, resulting in poor outcome and a 5-year survival rate of less than 5%. There are no effective therapies for PDAC, except for surgical resection which has a minor impact on survival. In order to improve clinical outcome, new therapeutic strategies are needed. PDAC is characterized by a dense desmoplastic reaction, primarily reflecting the activation of pancreatic stellate cells (PSC). PSC become activated in response to growth factors, oxidative stress and changes in tissue plasticity. Activated PSC within the PDAC stroma have an impact on the migration of immune cells towards malignant lesions, playing an important role in modulation of the crosstalk between neoplastic, stromal and immune cells. In PDAC, the ability of the immune system to identify and eliminate neoplastic cells is compromised, suggesting that an immunosuppressive environment is established. Immunotherapy can potentially be a powerful new component of PDAC treatment. However, in order to obtain immune-mediated elimination of PDAC, most likely immune stimulation must be combined with a strategy that overcomes the immunosuppressive environment. Further study of the mechanisms by which immunosuppression is initiated in PDAC, and ways to overcome it, will facilitate the development of this treatment option. Here, we will focus on unraveling the interactions between PSC, innate immune cells and tumor cells in order to identify new therapeutic targets. Experiments will be performed in vitro and in vivo.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: Van Audenaerde Jonas

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

Glioblastoma is the most common, malignant, primary brain tumor. One of the characteristics of this (and other) cancer(s) is suppression of the immune system. The aim of this research is to (re )activate the antitumoral functions of the innate immune cells in glioblastoma. This will be achieved by combining direct stimulation of the innate immune cells with alleviation of the protumoral and immunosuppressive tumor microenvironment.

Researcher(s)

• Promoter: Smits Evelien
• Fellow: De Waele Jorrit

Research team(s)

Project type(s)

• Research Project

Abstract

This project represents a research project 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: Smits Evelien
• Fellow: Smits Evelien

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 hand STK. UA provides STK research results mentioned in the title of the project under the conditions as stipulated in this contract.

Researcher(s)

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

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

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

The general aim is (1) to quantify exogenous boosting by means of an observational longitudinal study, (2) implement this result in newly adapted epidemiological models, (3) assess the population effects of vaccination against VZV and (4) apply this to inform a cost-utility analysis examining vaccination against VZV.

Researcher(s)

• Promoter: Beutels Philippe
• Co-promoter: Hens Niel
• Co-promoter: Smits Evelien
• Co-promoter: Van Damme Pierre

Research team(s)

Project type(s)

• Research Project

Abstract

The aims of this project are to test the implementation of non invasive imaging techniques to monitor tumor growth and/or elimination in an AML mouse model, as well as to test the efficacy of an autologous whole tumor cell vaccine. We will investigate if stable expression of reporter genes by murine AML cells will allow us to monitor tumor progression using bioluminescence and flow cytometry as non invasive techniques.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

This study aims to measure the impact of the sampling site on blood cell counts. For this purpose, blood samples will be drawn via an antecubital vein, a dorsal hand vein and the radial artery. Paired comparisons of red blood cell, platelet and white blood cell counts (including lymphocyte subpopulations using flow cytometry) will be made. Furthermore, we will assess the effect of cryopreservation on lymphocyte subpopulation counts.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

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

This project represents a research 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: Smits Evelien

Research team(s)

Project type(s)

• Research Project

Abstract

In this project we will examine the effect of an autologous tumor vaccine on survival in a mouse model of acute myeloid leukemia. The vaccine will consist of autologous tumor cells, injected together with Toll-like receptor ligands. The tumor and its environment will be studied using bioluminescence and flow cytometry.

Researcher(s)

• Promoter: Smits Evelien

Research team(s)

Project type(s)

• Research Project

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)

• Promoter: Van Tendeloo Vigor
• Fellow: Smits Evelien

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: Berneman Zwi
• Fellow: Smits Evelien

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