Research Jorrit De Waele

Abstract

Cell and gene therapies are revolutionizing the way cancer is treated. CAR-T cell therapies have demonstrated the ability to induce durable remissions or even achieve cures in patients with certain blood cancers that were in final stages, including leukemia and lymphoma. Despite these hopeful results in hematological malignancies, the application of CAR cellular therapies has been more challenging in solid tumors. Solid tumors have a complex tumor microenvironment (TME) that creates barriers to immune cell infiltration and function. This immune-suppressive niche is low in nutrients, highly acidic and hypoxic (lacking oxygen) due to the aberrant metabolism of tumor cells and growth pattern of the tumor. Accumulating data indicates that T cells and NK cells entering this hostile environment are rendered dysfunctional. Up to 90 percent of adult cancers consist of solid tumors, presenting a big need for new therapies. With our research, we aim to enhance the therapeutic potential of NK cell therapies for solid tumor patients in need of new treatment options. NK cells are cytotoxic cells from the innate immune system that can recognize and eradicate tumor cells swiftly. Their distinct advantages over T cells, including a superior safety profile and potential for allogeneic therapy, make NK cell treatments more economically feasible and logistically appealing, thereby broadening patient accessibility. Until now, efforts to enhance NK cell efficacy in cancer therapy have mainly focused on blocking inhibitory receptors, CAR engineering, or cytokine stimulation. However, recognizing the profound impact of the TME on NK cell metabolism, recent approaches aim to combine immunotherapy with metabolic manipulation to bolster cellular function. This growing awareness underscores the need for innovative engineering and gene editing to develop resilient cellular products capable of thriving in the challenging TME. In this project, we seek to (1) unravel metabolic interventions that boost the metabolic and functional resilience of NK cells in a hypoxic environment; (2) employ CRISPR-Cas9 to stably engineer NK cells based on our discoveries, thereby unlocking their potential in hostile tumor environments; and (3) validate the improved killing capacity and fitness of NK cells in hypoxic conditions using state-of-the-art assays. Driven by the need for novel therapeutic strategies that enhance the overall outcome for cancer patients, we aim to create an innovative NK cellular therapy product that is metabolically rewired to withstand the harsh and suppressive TME.

Researcher(s)

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

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Advanced stages of head and neck squamous cell carcinoma (HNSCC) often face relapse or metastasis, and a miserable prognosis. First-line immunotherapy, with/without chemotherapy, displays limited benefits due to low response rates and severe side effects in weakened patients, compounded by high costs. In response, I will investigate an innovative, well-tolerable, and cost-efficient combination strategy to enhance approved therapies for this hard-to-treat cancer. Non-thermal plasma (NTP) is a localized ionized gas therapy that has been shown to activate the immune system and to induce cell death via disrupting the redox balance. To date, clinical use of NTP does not have reported major side effects. In addition, a well-tolerated, repurposed drug, shown to modulate immunity and redox metabolism, will be explored for its potential synergy with NTP. Therefore, I hypothesize that this combination, by altering redox balance, will enhance the effectiveness of (immuno)therapies for HNSCC through increased oxidative stress, cell death, and anti-tumor immunity. I will use 3D in vitro cancer models, primary patient material, and in vivo mouse models to evaluate the tumor kinetics, immune engagement, and therapy effectiveness. Successful completion of my project will lead to a combination strategy of NTP with repurposing drugs to improve the efficacy of first-line HNSCC therapies, while supporting the patient's quality of life.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Bogaerts Annemie
• Co-promoter: De Waele Jorrit
• Fellow: Bauwens Mauranne

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, underscoring an unmet clinical need. The observation that HNSCC is one of the most inflamed and immune infiltrated tumor types, with an exceptionally high infiltration of natural killer (NK) cells, supports the potential of NK cells as a therapeutic agent for this indication. Importantly, immunometabolism is pivotal to immune responses, including for NK cells, yet, how the tumor microenvironment affects NK cell metabolism is largely unknown and identifying NK cell evasion mechanisms could unlock both current and new therapies for HNSCC. We hypothesize that the deregulated metabolism of HNSCC cells is a pleiotropic hallmark in evasion to NK cells. We postulate that these metabolic resistance mechanisms are dual. On the one hand, metabolic reprogramming of HNSCC cells could mediate intracellular resistance to killing by NK cells. On the other hand, the metabolically deregulated HNSCC cells modify the metabolic composition of the tumor microenvironment, resulting in suppression of NK cells due to metabolite disbalance. This ultimately promotes immune evasion and jeopardizes survival of HNSCC patients. Unravelling these resistance mechanisms bear the potential to push NK cell therapies forward. To this end, we will perform multi-omics analyses, target identification, genetic engineering and pharmacological targeting, 2D and 3D in vitro experiments, in silico validation and in vivo testing. First, we will elucidate the linchpins of intracellular metabolic pathways in HNSCC cell driving resistance to NK cell-killing by conducting a CRISPR knockout screen using a metabolism-focused library and the top targets will be validated using patient datasets and functional assays. Second, we will unravel the effect of extrinsic metabolites, secreted by HNSCC cells, on NK cell-mediated killing. The key metabolites responsible for reduced NK cellular killing capacity will be identified and validated correspondingly. Finally, the potential of metabolic interference of these targets to boost the next generation NK cell therapy for HNSCC, i.e. chimeric antigen receptor (CAR) NK cells, will be determined in vitro and validated in vivo. Concluding, the proposed project will enrich our understanding of evasion mechanisms to NK cells and will expedite the breakthrough of next-gen NK cell therapy for head and neck squamous cell carcinomas, with high potential for implementation in additional solid tumors types.

Researcher(s)

• Promoter: Wouters An
• Co-promoter: De Waele Jorrit
• Fellow: de Beukelaar Julie

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Prospects for cancer patients are certainly ameliorated in the past decade, especially thanks to the advances in the field of immunotherapy. However, it is important to note that many challenges remain. More specific, the majority of patients in need of better treatment options does not respond to immune checkpoint blocking therapy while CAR T cell therapy has only limited efficacy against solid tumours and on top causes severe side effects. Also, many tumours produce immunosuppressive cytokines like TGFβ, hampering current immunotherapy approaches. To address the challenges, our lab has developed over the past five years a TGFβ-resistant, Interleukin-15 producing CAR NK cell therapy which targets the CD70 protein. CAR NK cells have the important advantage that – contrary to CAR T cells – they do not cause severe side effects. Moreover, they can be produced as off-the-shelf therapy and do not require the same cumbersome production process as CAR T cells. The CD70 protein is also a ideal target since it is highly expressed in both leukaemia and solid tumours. This project has two main objectives. First, we want to gather the necessary preclinical data showing that our CAR NK cells are also successful against acute myeloid leukaemia. Secondly, we want to scale-up the production process of our CAR NK cells from research-grade to GMP-grade as this is a requirement for entering the clinical trial stage.

Researcher(s)

• Promoter: Smits Evelien
• Co-promoter: Campillo Davó Diana
• Co-promoter: De Waele Jorrit
• Co-promoter: Lion Eva
• Co-promoter: Van Audenaerde Jonas

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

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

The Research Council Prizes of the University of Antwerp are awarded every two years at the expense of the Special Research Fund University of Antwerp. They aim to honor a successful young postdoctoral researcher for a special contribution to his/her scientific field. J. De Waele is a laureate the Prize Vandendriessche.

Researcher(s)

• Promoter: De Waele Jorrit

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

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: Van Audenaerde Jonas

Research team(s)

• Center for Oncological Research (CORE)

Project website

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

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

Cellular cancer immunotherapy is on the rise to follow the footsteps of immune checkpoint inhibition as cancer immunotherapy breakthrough, yet only shows efficacy in haematological malignancies. Indeed, solid tumours impose various challenges on immune cells. Their tumour microenvironment (TME) is a metabolic wasteland that impairs effector immune cell functioning. Central in this TME is hypoxia, which is now recognized as barrier to immunotherapy due to effects on both tumour and immune cells. In this project, we focus on natural killer (NK) cells as effector immune cells with great potential as adoptive cell product due to inherent cytolytic capacities as well as safety and logistics profiles. Nonetheless, even when armoured with chimeric antigen receptors (CAR), NK cells fail to fully exert their function in hypoxia. Here, we will characterize and validate our lead for the development of (CAR) NK cells proficient in the hypoxic TME. This could propagate the development of next-generation of metabolically enhanced CAR NK cells against solid tumours.

Researcher(s)

• Promoter: De Waele Jorrit

Research team(s)

• Center for Oncological Research (CORE)

Project type(s)

• Research Project

Abstract

Cervical cancer (CC) patients, especially those with advanced disease, are urgently in need of new treatment options that can increase their survival rate and quality of life. A promising strategy is immunotherapy, however, only a minority of patients responds to it because the cancer has developed mechanisms that evade its effects. In recent years, the RANKL/RANK signaling pathway has been implicated as one such mechanism, as it allows many cancer types - including CC - to circumvent the immune response by disrupting the communication of the immune cells. Supported by our first results, we strongly believe that blocking the RANKL/RANK signal can release the brakes on the immune system and reinvigorate the tumor's susceptibility to immunotherapy. We therefore aim to expose the best possible immunotherapeutic partner(s) for anti-RANK(L) therapy in order to achieve the most optimal anti-tumor immune effects. For this, we have unique access to CC samples retrieved from patients before and after anti-RANKL monotherapy, which we will thoroughly investigate to reveal immune related changes. Thereafter, we will perform additional laboratory tests that will allow us to pinpoint one best-in-class anti-RANKL combination strategy, which we will further optimize in CC mouse models. Finally, this project will validate a novel imaging technique to stratify patients and monitor treatment response for this therapy, thereby minimizing treatment - and economic burden.

Researcher(s)

• Promoter: Van Dam Peter
• Co-promoter: De Waele Jorrit
• Co-promoter: Van den Wyngaert Tim
• Fellow: Verhoeven Yannick

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

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 an immunostimulant 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: De Waele Jorrit

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)

• Center for Oncological Research (CORE)

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

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